Mechanismen der Invasion von Karzinomen der Kopf- und Halsregion

BACKGROUND: Squamous cell carcinomas of the head and neck region are highly aggressive cancers. Survival of these patients critically depends on the prevention of locoregional recurrences. A locoregional relapse is associated with an invasive growth pattern of the primary cancer. Thus, we need to understand regulatory mechanisms of cancer invasion to be able to develop therapeutic strategies, which may help to improve survival in this patient population. METHOD: Literature search. RESULTS: Certain tumor proteases are required for invasive growth of head and neck cancers. DISCUSSION: It is our understanding that further indepth investigation of mechanisms involved in the regulation of protease expression may help to develop treatment strategies, which improve survival by reducing the invasive capacity of head and neck cancer cells.     

Potential prognostic and therapeutic role for angiogenesis markers in laryngeal carcinoma

Angiogenesis is a hallmark of cancer, fundamental to its growth. The 'angiogenic switch' occurs when pro-angiogenic factors are not balanced by anti-angiogenic factors. A correlation between angiogenic properties and oncological prognosis (for laryngeal squamous cell carcinoma (LSCC) too) was first hypothesized in the 1990s. An exhaustive literature review was performed to investigate available data on angiogenesis markers and their biological role and therapeutic potential in LSCC. The prognostic significance of microvascular density in LSCC was investigated with endothelial targets, e.g. CD105, CD34, and CD31. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), VEGF receptor 2, angiogenin, hypoxia-inducible factor 1, and other biological markers were also studied. Only anti-EGFR therapy has been approved by the USFood and Drug Administration (FDA) for head and neck carcinoma in recent years, while several agents interfering with VEGF and its receptors are being studied. Experimental findings indicate that anti-CD105 monoclonal antibodies efficiently inhibit tumor angiogenesis. There are two main ways to approach the vascular profile of solid malignancies: by inhibiting new vessel formation (anti-angiogenic therapy) or selectively damaging neoplastic vessels (vascular targeting therapy). In advanced LSCC, both these strategies seem promising and warrant further preclinical and clinical investigation.     

Coronoidectomy for the treatment of trismus in head and neck cancer patients

OBJECTIVES: Trismus is a common adverse effect of tumor extension or treatment for those with head and neck malignancy. Physical therapy is the mainstay of treatment, but many patients still fail to maintain adequate mouth opening. Coronoidectomy is a treatment option for those with trismus, and the purpose of this study was to evaluate the effectiveness of coronoidectomy in treating trismus refractory to physical therapy. STUDY DESIGN: Prospective case series. METHODS: Eighteen head and neck cancer patients with interincisal distances less than or equal to 20 mm underwent coronoidectomy after failing physical therapy for at least 3 months. All patients had undergone maximal radiation therapy, half after tumor resection. RESULTS: Postcoronoidectomy, mean interincisal distances improved 22.1 mm and 21.8 mm at 6 and 12 months, respectively, with all patients maintaining an interincisal distance greater than or equal to 35 mm. Tumor location, tumor histology, or the addition of surgical resection had no impact on outcome. CONCLUSION: Coronoidectomy is effective at improving trismus refractory to physical therapy in head and neck cancer patients.     

Gene Therapy for Head and Neck Cancer

Objectives/Hypothesis New treatment methods are needed for head and neck cancer to improve survival without increasing morbidity. Gene therapy is a potential method of improving patient outcome. Progress in gene therapy for cancer is reviewed with emphasis on the limitations of vector technology and treatment strategies. Given the current technological vector limitations in transmitting the therapeutic genes, treatments that require the fewest number of cells to be altered by the new gene are optimal. Therefore an immune‐based gene therapy strategy was selected in which the tumors were transfected with the gene for an alloantigen, human leukocyte antigen (HLA)–B7, a class I major histocompatibility complex (MHC). This would restore an antigen presentation mechanism in the tumor to induce an antitumor response. This gene therapy strategy was tested in patients with advanced, unresectable head and neck cancer. Study Design Prospective trial. Methods Twenty patients with advanced head and neck cancer who had failed conventional therapy and did not e‐press HLA‐B7 were treated with gene therapy using a lipid vector by direct intratumoral injection. The gene therapy product contained the HLA‐B7 gene and the β2‐microglobulin gene, which permits complete e‐pression of the class I MHC at the cell surface. Patients were assessed for any adverse effects, for changes in tumor size, for time to disease progression, and for survival. Biopsy specimens were assessed for pathological response, HLA‐B7 e‐pression, apoptosis, cellular proliferation, CD‐8 cells, granzyme, and p53 status. Results There were no adverse effects from the gene therapy. At 16 weeks after beginning gene therapy, four patients had a partial response and two patients had stable disease. Two of the tumors completely responded clinically, but tumor was still seen on pathological examination. The time to disease progression in the responding patients was 20 to 80 weeks. The median survival in patients who completed gene therapy was 54 weeks, compared with 21 weeks in patients whose tumors progressed after the first cycle of treatment. One patient survived for 106 weeks without any additional therapy. HLA‐B7 was demonstrated in the treated tumors, and increased apoptosis was seen in the responding tumors. Conclusion Significant advances have been made in the field of gene therapy for cancer. Alloantigen gene therapy has had efficacy in the treatment of cancer and can induce tumor responses in head and neck tumors. Alloantigen gene therapy has significant potential as an adjunctive treatment of head and neck cancer.     

头颈鳞癌血管生成与颈淋巴结转移相关性研究

目的 :探讨头颈鳞癌血管生成与其颈淋巴结转移的关系以及血管内皮生长因子(VEGF)在头颈鳞癌血管生成中的作用。方法 :应用免疫组化SABC法检测 5 8例头颈鳞癌组织中微血管密度 (IMVD)及VEGF的表达。结果 :5 8例头颈鳞癌组织中IMVD为 2 3.93± 8.77,肿瘤分化程度 ,高与中、高与低间 ,IMVD差异有显著性意义 (均P <0 .0 5 ) ;中与低间 ,差异无显著性意义 (P >0 .0 5 )。颈淋巴结转移组IMVD(2 7.92± 9.11)明显高于非转移组 (2 0 .6 9± 7.0 8) ,其差异有显著性意义 (P <0 .0 1)。癌组织中VEGF表达与瘤内IMVD呈正相关 (rs=0 .4 87,P <0 .0 1)。结论 :瘤内IMVD可作为预测头颈鳞癌颈淋巴结转移的一个重要指标 ;VEGF可促进头颈鳞癌血管生成。     

Percutaneous embolization for cervicofacial neoplasms and hemorrhages

OBJECTIVE: To retrospectively assess the effectiveness of percutaneous embolization for curative, preoperative or palliative management of hypervascular neoplasms, vascular malformations and bleedings of the head and neck area. METHODS: A retrospective 8-year analysis of outcomes in 85 patients undergoing preoperative embolization for tumors or vascular lesions of the head and neck or embolization for refractory tumor bleeding and epistaxis at our hospitals was performed by reviewing case records. Outcome of the preoperatively embolized patients was defined as successful if intraoperative bleeding was <500 ml and/or postinterventional angiogram showed complete occlusion of all tumor-feeding or bleeding vessels. RESULTS: Complete preoperative tumor embolization was achieved in 83.5% of the patients. Partial embolization was possible in 10.5%. All tumor bleedings refractory to conservative therapy and bleedings from epistaxis showed a successful outcome. CONCLUSIONS: In vascular lesions and tumors of the head and neck, preoperative percutaneous embolization improved the surgical outcome, reduced intraoperative blood loss significantly and facilitated tumor resectability. Cervicofacial bleeding resulting from a tumor, vascular malformation or epistaxis can be managed effectively by endovascular techniques.     

Hyercalcaemia in head and neck squamous cell carcinoma

PURPOSE OF REVIEW: Patients with advanced head and neck cancer are being treated with chemo-radiotherapy, and life is being prolonged, with or without persistent disease, for longer than was previously. Hypercalcaemia may present in patients with advanced or disseminated head and neck cancer, and, as such, these patients may present to a larger variety of clinicians for advice concerning their symptoms and illness. Modes of presentation of hypercalcaemia and treatment strategies are reviewed. RECENT FINDINGS: There were previously few large series of head and neck cancer patients diagnosed with hypercalcaemia, which may or may not have been related to their cancer being treated. Investigations, by way of blood/serum calcium level, may identify such patients. Patients with cancer-related hypercalcaemia have a poor prognosis, but many may respond temporarily to treatment when offered, with an improvement of their quality of life and death. SUMMARY: Hypercalcaemia should and must be considered in all patients who have or possibly have a diagnosis of a head and neck cancer and who present unwell with symptoms of fatigue, lethargy and somnolence. Investigation must include serum calcium (corrected for serum albumin binding) and parathyroid hormone level. Patients may be treated by a combination of rehydration and bisulphonate therapy until the serum calcium is reduced to a level below 3 mmol/l. The majority of patients diagnosed with hypercalcaemia due to head and neck malignancy die of their diseases in the short term, but some may enjoy a prolongation of life with reasonable quality if diagnosed and treated aggressively.     

Major histocompatibility gene therapy: the importance of haplotype and beta 2-microglobulin

OBJECTIVES/HYPOTHESIS: Alloantigen gene therapy with the genes for the Class I major histocompatibility complex (MHC) HLA-B7 and beta 2-microglobulin in HLA-B7-negative patients has potential efficacy in the treatment of head and neck cancer, although the mechanism of response is unclear. Whether tumor regression is due to a response to HLA-B7 in HLA-B7-negative patients (i.e., due to "foreign" antigen) or simply to MHC overexpression is unknown. Therefore, a mouse model was used to compare tumor growth following syngeneic MHC transfection to alloantigenic MHC transfection. The importance of the beta 2-microglobulin gene was also evaluated. STUDY DESIGN: Prospective animal study. METHODS: The head and neck cancer cell line SCC-VII that grows in immunocompetent C3H mice, which are MHC haplotype H2-K, was used. Stable transfections were made with H2-K, H2-K, and beta 2-microglobulin in the SCC-VII cells. To test the importance of MHC "foreignness," mice were injected with SCC-VII cells, SCC-VII plus H2-K plus beta 2-microglobulin transfected cells, and SCC-VII plus H2-K plus beta 2-microglobulin transfected cells. To evaluate beta 2-microglobulin, mice were injected with SCC-VII cells, SCC-VII plus H2-K plus beta 2-microglobulin transfected cells, SCC-VII plusH2-K transfected cells, and SCC-VII plus beta 2-microglobulin transfected cells. Tumor growth in all groups was compared statistically. RESULTS: Major histocompatibility complex foreignness was a part of the antitumor response. Foreign MHC routinely abrogated tumor growth, whereas syngeneic MHC only slowed tumor growth. beta 2-microglobulin aided the MHC tumor inhibition but did not inhibit tumor without the MHC. CONCLUSION: The antitumor response was greater when the MHC gene used was foreign. beta 2-microglobulin increased the efficacy of MHC gene therapy. Both of these findings are important when designing clinical trials of immunologically based gene therapies for head and neck cancer.     

Mononuclear phagocytes in head and neck squamous cell carcinoma

The head and neck squamous cell carcinoma microenvironments contain many immune cells and their secretory products. Many of these cells belong to the mononuclear phagocyte system. The aim of this review is to study the interactions between mononuclear phagocytes and head and neck squamous cell carcinoma tissue. The role of inflammation in tumours and the cytokine interleukin-6 will be highlighted. Future therapy strategies in the treatment of head and neck cancer might be directed towards mononuclear phagocytes and their cytokine production.     

Acute haemorrhage in patients with advanced head and neck cancer: value of endovascular therapy as palliative treatment option

AIMS: Acute or subacute haemorrhage is one of the most frightening complications in patients suffering from advanced head and neck cancer. Few articles report experience with superselective endovascular therapy for this purpose. Is endovascular therapy underestimated in the field of palliative head and neck cancer therapy? This study set out to investigate this question. PATIENTS AND METHODS: A review was undertaken of the clinical courses of seven patients (six men, one woman) suffering from incurable, advanced head and neck cancer (four pharyngeal, two laryngeal, one neck) and treated with superselective endovascular strategies as an emergency procedure for acute bleeding. RESULTS: All patients were successfully treated without evidence of neurological complication. Patients reached a median survival of 20 weeks (range eight-168 weeks). Following endovascular treatment all patients were discharged from the hospital within several days. Three patients survived almost free of symptoms for several weeks and were able to stay at home with their families until their death. CONCLUSION: We conclude that in the field of palliative care, superselective endovascular therapy deserves to be considered alongside standard treatment options for the management of acute haemorrhage from advanced head and neck cancer.     

Meta-tetra(hydroxyphenyl)chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck

OBJECTIVE: Photodynamic therapy (PDT) is a relatively new treatment modality for various types of cancer, including cancer of the head and neck. The advent of the second-generation photosensitizers such as meta-tetra(hydroxyphenyl)chlorin (mTHPC) (Foscan; Scotia Pharmaceuticals, Stirling, Scotland), which are more effective and less phototoxic to the skin than their forerunners, now makes this treatment a feasible alternative to surgery or radiotherapy in specific cases. To evaluate the long-term outcome of this therapy for squamous cell carcinomas of the head and neck, we treated patients with PDT using mTHPC. DESIGN: Prospective study. SETTING: Tertiary cancer referral center. PATIENTS: Twenty-five patients with 29 T1-T2 N0 tumors of the oral cavity and/or oropharynx. INTERVENTION: Photodynamic therapy. MAIN OUTCOME MEASURE: Complete local tumor remission. RESULTS: The mean follow-up of the patients after treatment was 37 months. In 25 (86%) of 29 tumors, a complete remission of the primary tumor was obtained. In the 4 recurrences, salvage was achieved by conventional therapy. In none of the patients was any long-term functional deficit detected. CONCLUSIONS: This study confirms that PDT is a powerful treatment modality that could be considered as an alternative to surgery or radiotherapy in specific cases of head and neck cancer. The major advantage of PDT over these conventional therapies is the reduction in long-term morbidity. Radiotherapy or surgery could be reserved for salvage therapy in the event of a recurrence or second primary tumors.     

Hemmung zellulärer SignaltransduktionskaskadenEine zukünftige antiinvasive Therapiestrategie für Karzinome in der Kopf- und Halsregion

Background. Squamous cell carcinomas of the head and neck are considered to be highly aggressive cancers. The 5-year survival rate of patients with this disease depends on whether a locoregional relapse occurs and if so, how early after the initial treatment. Disease was found to relapse more frequently in patients suffering from cancers with an invasive growth pattern. It was therefore concluded that cancer cell invasion influences the patient's survival. While considerable efforts are made to develop treatment regimens for relapsing disease, a novel approach consists of the prevention of the disease recurrence through the inhibition of cancer cell invasion. Method. Literature search. Results. We summarize in this article the mechanisms of tumor invasion, focusing on the regulation of tumor proteases, which are essential for cancer invasion, and provide an overview of preliminary results with novel anti-invasive treatment strategies. Conclusion. Novel anti-invasive treatment regimens based on an understanding of molecular cancer invasion mechanisms may be used in the future to treat patients with head and neck cancers.     

Genetic predisposition for the development of head and neck carcinomas

BACKGROUND: While cigarette smoking and chronic alcohol consumption are the major risk factors for the development of head and neck cancer, it is assumed that genetic factors contribute to risk. Glutathione-S-transferase GSTM1 AB, GSTM3 BB and GSTP1 AA as well as TNF genotypes were determined from leucocyte DNA in 392 patients with head and neck carcinoma and 216 controls, with added immunohistochemical studies. Comparative genomic hybridization was used to screen for genetic alterations in the tumor tissue. RESULTS: While the frequency of GSTM1 AB was significantly lower in all head and neck carcinomas compared with controls, GSTM3 BB was significantly lower in the laryngeal and GSTP1 AA in the oral cavity/pharyngeal carcinoma cases; the frequency of the TNFb3 allele was higher in the laryngeal cases. Chromosomal alterations were specific for head and neck carcinomas, differing both in well differentiated and undifferentiated and in metastasizing and non-metastasizing tumors. CONCLUSIONS: Allelism at GST gene loci mediates susceptibility to head and neck carcinomas: GSTM1 AB is associated with a lower risk for all head and neck carcinomas, GSTM3 BB only for laryngeal carcinomas and GSTP1 AA only for oral cavity/pharyngeal carcinomas. The TNFb3 allele was significantly more frequent in laryngeal cancer patients. The genetic alterations in the tumor tissue are in line with the "tumor progression model". Genetic conditions are important from the first exposure with carcinogens up to late genetic events in the tumor tissue.     

Anthrapyrazoles and Interstitial Laser Phototherapy for Experimental Treatment of Squamous Cell Carcinoma

Interstitial laser therapy (ILT) is an effective palliative treatment for advanced head and neck cancer, but recurrence often is seen at the margin. The objective of the current study was to test combined drug and laser therapy as an experimental approach for improved treatment of human squamous cell carcinoma (SCCA). Human SCCA tumor transplants were grown in nude mice and injected with the photosensitive anthrapyrazole CI-941 before ILT. Intralesional drug injections alone at levels ranging from 60 to 1200 μg/gm of tumor induced a growth delay at the higher doses, but recurrence was seen in all 35 tumors tested. SCCA tumor transplants injected with 240 μg/gm CI-941 followed after 4 hours by ILT with the KTP532 laser led to a complete response rate of 72% (21/29) compared with 45% (13/29) for ILT alone. Laser chemotherapy was a significant improvement compared with ILT when partial and complete responses were combined (P < 0.03). The results provide preclinical evidence that laser chemotherapy may become a useful minimally invasive treatment for advanced squamous cell carcinoma of the head and neck.     

Head and neck cancer recurrence and mortality in nonselective cyclooxygenase inhibitor users

OBJECTIVE: To determine whether ongoing use of a cyclooxygenase (COX) inhibitor is associated with a reduction in mortality and disease recurrence after head and neck cancer treatment. DESIGN: Retrospective case-control study. Patients A total of 325 potential subjects with head and neck squamous cell carcinoma were identified using an electronic patient database. Main Outcome Measure The rate of COX inhibitor use among patients who had died or whose disease had recurred (cases) was compared with the rate of use among survivors or those without recurrence (controls). The comparison was controlled for tumor site, tumor stage, treatment received, age, sex, race, smoking, and alcohol use. RESULTS: The 325 patients were compared by logistic regressions, with recurrence rate and survival status as the dependent variables. There was no difference in COX inhibitor exposure between patients with recurrence and those with no recurrence (P = .42) or between survivors and those who died of disease (P = .66). The median survival of COX inhibitor users, however, was 96 months, compared with 47 months in nonusers. The only independent variable with a significant impact on recurrence and survival was tumor stage at the time of diagnosis. CONCLUSIONS: Although preliminary in vitro studies suggest an antitumor effect of COX inhibitors in head and neck cancer, this study found no difference in head and neck cancer recurrence or survival in nonselective COX inhibitor users vs nonusers. A randomized, double-blinded controlled trial is needed to determine if COX inhibitors are an effective chemopreventive therapy in patients with head and neck cancer.     

Progression of head and neck cancer in an in vitro model

OBJECTIVE: To identify alterations in angiogenesis and cell cycle regulation as preneoplastic cells progress to cancer in an in vitro model of head and neck tumor progression. METHODS: Immortal human gingival keratinocyte (IHGK) cells (preneoplastic) were derived from normal oral keratinocytes and were immortalized with human papillomavirus 16. Transformation of IHGK cells with a carcinogen (NNK, 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone) gave rise to IHGKN cells. We determined the growth rates, cell cycle phase, expression of cell cycle regulators, and expression of vascular endothelial growth factor along with the organotypic features of these cells and compared them with characteristics of head and neck cancer cells. RESULTS: IHGK and IHGKN cells grown in raft culture were morphologically similar to severe dysplasia and carcinoma, respectively. The proportion of cells in G(0)/G(1) was similar between IHGK and IHGKN. However, the proportion of IHGK cells was 35% greater in S phase as compared with the IHGKN cells, while a greater percentage (40%) of IHGKN cells were in G(2)/M. The expression of the other cell cycle regulators tested was unchanged. IHGK cells secreted less vascular endothelial growth factor on day 1 when compared with IHGKN (50.6 vs 245.6 pg/mL), along with a lower overall production rate (79% vs 133%). CONCLUSIONS: Transformation of IHGK cells resulted in the activation of vascular endothelial growth factor associated with angiogenesis. Inactivation of the G(1) cell cycle regulation occurred during immortalization and before transformation, and was sustained after carcinogen exposure. These alterations correspond to changes observed in patients with head and neck squamous cell carcinoma. This model can be useful in testing novel therapeutic and preventive strategies.     

低电压电化学疗法对头颈部肿瘤裸鼠移植瘤抑制作用的研究

目的：探讨低电压电化学疗法对头颈部肿瘤的治疗意义。方法：于裸鼠下颌皮下接种人头颈部鳞状上皮细胞癌YCU—N861细胞系细胞,制成移植瘤模型。局部注射博来霉素（BLM）20μg／只,继以50V、100V的电压刺激（EP）,观察肿瘤生长情况,并测量其体积。9d后取肿瘤组织,常规苏木精-伊红染色及免疫组织化学染色后观察。结果：BLM和EP联合应用能明显抑制肿瘤细胞的增殖,联合治疗组（BLM＋EP）与BLM组、EP组和空白对照组比较,均差异有统计学意义（均P〈0．01）;BLM＋EP组肿瘤生长发育迟缓,明显受到抑制,组织学表现为坏死出血征象,有丝分裂指数和免疫组织化学Ki67染色标记指数分别为9．90±3．48、2．28±2．61,与BLM组（34．33±6．60、6．41±3．59）、EP组（58．75±8．87、8．85±3．25）及对照组（73．25±11．95、11．10±3．67）比较,差异有统计学意义（均P〈0．01）。结论：低电压电化学疗法在头颈部肿瘤的治疗方面具有广阔的应用前景。     

Outcomes research in head and neck cancer

Quality of life (QOL) considerations are uniquely important in head and neck oncology outcomes research due to the multidimensional impact of these tumors and their treatment. Patient variables, tumor variables and treatment variables must be considered comprehensively in order to maximize the validity of QOL outcome measures. There are a multitude of QOL instruments, which can be classified into: (1) general measures of health-related QOL, (2) general QOL instruments for patients with cancer, (3) disease-specific instruments for patients with head and neck cancer, (4) treatment-specific instruments and (5) symptom-specific instruments. This article will highlight commonly used validated QOL instruments in head and neck oncology.     

The effect of hyperbaric oxygen on growth of human squamous cell carcinoma xenografts.

Hyperbaric oxygen is an important adjunct to the treatment of patients with head and neck cancer with existing or recurrent wound healing problems. Anecdotal clinical observations and a recent study of chemically induced oral cancer in hamsters have raised concern that hyperbaric oxygen therapy may accelerate tumor growth in such patients. This study evaluated the effect of hyperbaric oxygen therapy on the growth of human squamous cell carcinoma xenografts in a proved animal model. Fresh tumor specimens from three patients with head and neck squamous cell carcinoma of varying degrees of differentiation were first subcutaneously transplanted into a nude mouse host. Growing xenografts were then transplanted into one of three mouse groups. Half of the mice in each group were given hyperbaric oxygen therapy. The transplant volume as an index of tumor growth was measured in controls and mice given hyperbaric oxygen therapy six times during the 3-week course. Xenograft growth was almost linear in all mice. No statistical difference in overall group mean growth rates was observed in mice given hyperbaric oxygen or control mice regardless of the degree of tumor differentiation. Xenograft tissue from all mice was microscopically examined for tumor mitotic indices and degree of differentiation. This study suggests that hyperbaric oxygen therapy has no effect on established tumor xenograft growth.     

Current thoughts on the role of chemotherapy and radiation in advanced head and neck cancer

PURPOSE OF REVIEW: The management of advanced malignancies of the head and neck continues to be a challenging clinical problem. During the last three decades, the traditional treatments of surgery and/or radiation have not yielded significant improvements in survival in this patient population. In addition, surgery for advanced disease can create significant functional and cosmetic defects that adversely impact a patient's quality of life. Newer "organ preservation" approaches using chemotherapy and radiation are currently being studied in an attempt to improve survival while maintaining the functional integrity of the disease site. RECENT FINDINGS: Recent studies have demonstrated that for advanced head and neck squamous cell cancers, concurrent chemoradiation is superior to radiation alone for local tumor control and perhaps overall survival. With the exception of laryngeal cancer, phase III data comparing chemoradiation with surgery is lacking for most head and neck subsites. However, comparisons with historical controls suggest that chemoradiation strategies may offer improved outcomes when compared with more traditional treatment regimens. SUMMARY: This review emphasizes recent phase III trials that support the use of chemoradiation strategies in the treatment of advanced head and neck squamous cell cancers.