Evidence-based radiation oncology in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Historically, radiation therapy (RT) has been an available treatment option for patients with early resectable head and neck squamous cell carcinoma (HNSCC) and the sole therapy for those with unresectable or inoperable disease. Recently, four noteworthy strategies have emerged for the improvement of therapeutic outcome in the curative treatment of HNSCC: they include the development of altered fractionation radiotherapy, integration of chemotherapy with radiotherapy, incorporation of intensity-modulated radiotherapy and the introduction of targeted biological therapy. These strategies are briefly reviewed in an effort to help interpret evidence-based data and to facilitate clinical-decision making in a clinical context. MATERIALS AND METHODS: For patients with early stage HNSCC no level 1 study exists in which radiation therapy is compared with conservative surgery for the evaluation of local control or survival. Only evidence from prospective and retrospective cohort studies is available to evaluate the role external radiotherapy and/or brachytherapy currently play in limited disease. For patients with locally advanced HNSCC the recommendations to address the questions about better treatment in resectable and unresectable tumors are based on more than 100 randomized Phase III trials included in six meta-analyses on chemo-radiotherapy and/or altered fractionation. Data from phase II trials and cohort studies help interpret the advances in intensity-modulated radiotherapy. RESULTS: External radiotherapy and/or brachytherapy are crucial treatment options in patients with early stage HNSCC. For patients with locally advanced HNSCC, where outcome with conventional radiotherapy is poor, meta-analyses and collective data showed that loco-regional control may be improved at high level of evidence by altered fractionation radiotherapy, chemo-radiotherapy with concomitant approach or association of selected hypoxic cell radiosensitizer with radiotherapy. For these patients, overall survival may be improved at high level of evidence by concomitant chemo-radiotherapy or hyperfractionated RT delivered with increased total dose. Also EGFR-inhibitors (cetuximab)-radiotherapy strategy offers at a lower level of evidence better loco-regional control and overall survival than radiotherapy alone. Chemo-radiotherapy programs can achieve an improved larynx-function preservation program without the risk of overall survival reduction, for patients with larynx or hypopharynx tumors who are candidates to radical surgery followed by radiotherapy. Recently, strong evidence for an improved outcome for high-risk resected patients has been shown by the use of adjuvant concomitant chemo-radiotherapy. Despite improved results, a higher severe toxicity has been largely evidenced with concomitant chemo-radiotherapy by reducing the gain in the therapeutic index with new treatment strategies. Three-dimensional conformal radiotherapy is the minimal standard of technique in HNSCC: however, as advances are promising, intensity-modulated radiotherapy should be largely implemented. CONCLUSIONS: Stepwise improvements in HNSCC non-surgical therapy have shown favorable impact on loco-regional control and overall survival. However, despite hundreds of clinical trials in patients with advanced disease, there is no absolute consensus about patient selection for altered fractionation regimens, type of chemo-radiotherapy association, radiation or chemotherapy dose schedule. Nevertheless, many well-conducted clinical studies have expanded therapy options besides standard radiotherapy and have contributed to defining the evolving standard of care for patients with HNSCC.     

Targeted therapy for squamous cell carcinoma of the head and neck

Targeted agents have emerged as novel drugs in the oncology field based on our understanding of the biology of individual malignancies, and have had a promising impact in several tumors. Squamous cell carcinoma of the head and neck (SCCHN) is a common disease with little progress made in survival over the past few decades. SCCHN is characterized by overexpression of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), both of which appear to have a prognostic value. Hence these receptors and their downstream pathways make attractive therapeutic targets. This review discusses targeted therapies currently being evaluated for their role in squamous cell carcinoma of the head and neck.     

头颈部鳞癌放射治疗现状与展望

在过去的20年,头颈部鳞癌（squamous cell careinoma of the head and neck,SCCHN）的手术、放疗和化疗等都有了重大进展。手术治疗从扩大根治转向保留器官或器官功能保护,如半喉切除、喉重建和激光治疗。适形调强放疗（intensity—modulated radiationtherapy,IMRT）和改变分割照射方法则使放疗的耐受性和临床疗效得到了提高。此外,随着有效化疗药物的出现,其在局部晚期SCCHN综合治疗中的作用受到越来越多的重视。     

头颈部鳞状细胞癌靶向治疗进展

每年全世界大约有65万例新的头颈癌病例出现,其中绝大多数是头颈部鳞状细胞癌。晚期头颈部鳞状细胞癌的治疗需要综合治疗,尽管放化疗及手术治疗手段在不断发展,但是预后仍不理想且具有一定的毒副反应。靶向治疗是目前治疗研究头颈部鳞癌的热点,其在针对头颈部鳞癌的治疗特别是对局部晚期或复发/转移性头颈部鳞癌治疗中展现出了希望。本文综述了靶向治疗的最新进展。     

High-dose intra-arterial cisplatin boost with hyperfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the tolerance and efficacy of intra-arterial (IA) cisplatin boost with hyperfractionated radiation therapy (HFX-RT) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Forty-two patients with locally advanced primary SCCHN were treated on consecutive phase I/II studies of HFX-RT (receiving a total of 76.8 to 81.6 Gy, given at 1.2 Gy bid) and IA cisplatin (150 mg/m(2) received at the start of and during RT boost treatment). RESULTS: Acute grade 3 to 4 toxicities were as follows: grade 4 and grade 3 mucosal toxicity occurred in three (7%) and 31 patients (69%), respectively, and grade 3 hematologic, infectious, and skin events occurred in one patient each. Eight of 24 patients (33%) were unable to receive a second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). Thirty-seven patients (88%) experienced complete response (CR) at primary site. Twenty-nine (85%) of 34 patients presenting with nodal disease experienced CR. The actuarial 2-year rates of locoregional control and disease-specific and overall survival are 73%, 63%, and 57%, respectively, with a median active follow-up of 30 months. CONCLUSION: In this highly unfavorable subset of patients, these results seem superior to previously reported chemoradiation regimens in more favorable patients. Use of a second dose of IA cisplatin boost was associated with increased toxicity without obvious therapeutic gain. This novel strategy allows for an incremental increase in the treatment intensity of the HFX-RT regimen recently established as superior to once-a-day RT.     

Concomitant boost technique using accelerated superfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck.

Of 142 patients irradiated for American Joint Committee on Cancer Stage III or IV head and neck carcinoma, 100 patients were eligible for analysis with a minimum follow-up of 12 months. In one group, 50 patients were treated with conventional once-a-day (QD) fractionation to doses in excess of 6600 cGy. The other 50 patients were treated prospectively with accelerated superfractionated radiation therapy using a concomitant boost twice-a-day schedule (BID). Patients received conventional fractionation (180 cGy/fraction) combined with a boost field of 160 cGy/fraction BID after a 4-hour to 6-hour interval 3 days per week during part of their treatment course. After 3 years, locoregional tumor control was 62% in the BID group versus 33% in the QD group (P = 0.003). Disease-free survival was 60% and 30%, respectively, for the BID and QD groups (P = 0.002), and adjusted survival was 66% and 38%, respectively, for the BID and QD groups (P = 0.03). Overall survival approached statistical significance in favor of the BID group (P = 0.06). Complete tumor responses were observed in 63% of patients treated in the BID group 1 to 3 months after completion of radiation therapy. Of these, 84% remain free of local recurrence. Of the 19 patients with persistent disease 1 to 3 months after treatment, 47% remain locally controlled. Superfractionated accelerated radiation therapy produced superior local control and disease-free and adjusted survival rates relative to a group of patients treated QD.     

Multimodality therapy for unresectable squamous cell carcinoma of the head and neck

Eighteen patients with unresectable Stage III or IV squamous cell carcinoma of the head and neck were treated with induction therapy consisting of sequential methotrexate and 5-fluorouracil. This was followed by full course radiation therapy and radical neck dissection for those with residual neck disease. Those with local control were then treated with vinblastine, bleomycin, and cisplatin (VBP). Although 79% of patients achieved a partial or complete response to chemotherapy, only 50% of patients achieved local control. Marked mucositis limited the dose and schedule of radiation therapy. The methotrexate and 5-fluorouracil combination appears to be too toxic for multimodality therapy of advanced head and neck cancer.     

Concomitant vinorelbine and radiation in head and neck squamous cell carcinoma in vitro

Concomitant chemoradiotherapy has been used for locally advanced head and neck squamous cell carcinoma (HNSCC) particularily with cisplatin, 5-FU, methotrexate, bleomycin and taxanes. Vinorelbine is a semisynthetic vinca alcaloid, which causes a block in the G2/M phase of the cell cycle. HNSCC cell lines have previously been reported to be sensitive to vinorelbine in nanomolar concentrations. In the current study the effect of vinorelbine as a radiosensitizer in vitro was studied and eight recently established head and neck SCC cell lines of the UT-SCC-series were tested. Vinorelbine concentrations of 0.4-1.6 nM were used, corresponding to the IC70, IC50 and IC30 values of each cell line, resulting in 30%, 50% and 70% inhibition in clonogenic survival. The desired concentrations of vinorelbine were added to the medium and the cells were plated in 96-well culture plates in this solution. The plated cells were irradiated 24 h later with 4MeV photons generated by a linear accelerator and incubated at 37 degrees C with 5% CO2 for 4 weeks. Thereafter, the number of wells containing coherent, living colonies, consisting of 32 cells or more, was counted. The plating efficiency was calculated and the fraction survival data were fitted to the linear quadratic model [F = exp[-(alphaD + betaD2)]]. An additive effect of combining vinorelbine and irradiation could be demonstrated. The dose-dependent decrease in survival was seen at vinorelbine doses of 0.4-1.6 nM in all cell lines tested.     

头颈部恶性肿瘤的靶向治疗进展

手术和放疗技术的进步对局部晚期或晚期头颈部肿瘤患者并未带来长期生存率的明显提高,靶向治疗日渐成为包括头颈部肿瘤在内的重要治疗选择。表皮生长因子受体在头颈部肿瘤中有较高水平表达,其表达情况与疾病的预后密切相关,并成为靶向治疗的重要靶点。针对该受体的抑制剂在头颈部肿瘤中应用取得了令人满意的疗效,目前临床资料显示该类药物单药及与其它治疗手段的联合在头颈部肿瘤中应用均取得较好疗效,但是靶向药物的作用机制及其敏感性的预测分子尚不明确。针对复发转移的头颈部肿瘤的二线治疗的Ⅲ期临床正在进行,与其他治疗手段的联合治疗的方法正在探索和验证,新的预测分子也在涌现。本文将对以上内容进行综述。     

Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation

Background and purpose

There is a great need to improve the outcome of locoregionally advanced squamous cell carcinomas of the head and neck (HNSCC). Standard treatment includes a combination of surgery, radio- and chemotherapy. The addition of molecular targeting agents to conventional treatment may improve outcomes. In this study the Raf inhibitor sorafenib was used to increase the radiosensitivity of HNSCC cell lines.

Material and methods

In a panel of six cell lines (A549, FaDu, UTSCC 60A, UTSCC 42A, UTSCC 42B, UTSCC 29) radiosensitivity was measured by colony formation assay and apoptosis and cell cycle analysis were performed by flow cytometry. DNA repair was analyzed by 53BP1 immunohistochemistry.

Results

Sorafenib added prior to irradiation resulted in an increased cellular radiosensitivity (DEF_0.5 = 1.11–1.84). Radiosensitization was not caused by an enhanced rate of apoptosis or cell cycle effects. In contrast, sorafenib was shown for the first time to block the repair of DNA double-strand breaks (DSB).

Conclusion

Our data suggest that sorafenib may be used to overcome the radioresistance of HNSCC through the inhibition of DSB repair.     

Postoperative concurrent radiation and chemotherapy for squamous cell carcinoma of the head and neck

Conclusions The addition of concurrent cisplatin to postoperative radiotherapy significantly improves disease-free survival of patients with high-risk cancer of the head and neck, at the cost of significantly increased acute and total toxicity. Despite the improvement in disease-free survival, this preliminary analysis demonstrated no significant improvement of locoregional control or overall survival.     

Intensity modulated photon and proton therapy for the treatment of head and neck tumors.

PURPOSE: A comparative treatment planning study has been performed between intensity modulated photon and proton therapy to investigate the ability of both modalities to spare organs at risk in the head and neck region while keeping target dose homogeneous. Additional advantage of reducing the spot size for IMPT was also investigated. The treatment planning comparison was extended by varying the number of fields to study its effect on the performance of each modality. Risks of secondary cancer induction were also calculated for all modalities. MATERIALS AND METHODS: Five planning CTs were selected for the study. Four different constraints were set to the organs at risk in order to measure the resulting dose homogeneity in the target volume. Five and nine field plans were made for IMXT and 3, 5 and 9 field plans were made for IMPT, for both spot sizes. Dose homogeneity as a function of the mean parotid dose was visualized using a 'pseudo' Pareto-optimal front approach. Risks of secondary cancer were estimated using the organ equivalent dose model. RESULTS: Critical organs were best spared using 3-field IMPT and, at least for IMPT, little advantage was seen with increasing field numbers. Reducing the spot size does give an advantage. In contrast, there was a significant advantage in going from 5 to 9 fields for IMXT. Secondary cancer risk was lowest for the IMPT plans with reduced spot size, for which normal tissue received the lowest integral dose. Interestingly, although integral dose remained the same, increasing the number of IMPT fields increased the secondary cancer risk, due to the increased volume of tissue irradiated to low dose. CONCLUSIONS: IMPT has a better ability to spare organs at risk than IMXT for the same dose homogeneity. It also significantly reduced the estimated risk of secondary cancer induction and the use of small numbers of fields further increased this advantage. Given that target homogeneity and normal tissue sparing were equally good with the 3 field IMPT, there appears to be a clear rationale to deliver small numbers of fields for IMPT.     

Treatment of locally advanced squamous cell carcinoma of the head and neck with concurrent bleomycin and external beam radiation therapy.

Nineteen patients with advanced head and neck cancer were treated with bleomycin (15u BM and irradiation (180 rad, 5d/week, 5040 rad) and have analyzed the effects. Most patients went on to further radical treatment. Both epithelial toxicity and tumor regression seemed enhanced. Approaching 1 year minimum follow-up (2 years maximum) crude survival is 68% and disease-free survival is 57%. Late complications do not seem to be enhanced. Regression in advanced nodal disease was less impressive.     

Microsatellite instability in squamous cell carcinoma of the head and neck.

Genomic instability or microsatellite instability (MI) in simple repeated sequences was initially recognised in colonic carcinomas and subsequently in other tumours. MI has been associated with mutations in genes concerned with replication and DNA repair. We investigated 34 microsatellite markers in squamous cell carcinoma of the head and neck (SCCHN). Fifty-six tumours, were studied, of which 25 were investigated with ten or more microsatellite markers. In this study we consider two or more microsatellite alterations in a tumour to be diagnostic of MI. We demonstrated that 7/25 (28%) of the tumours had MI at two or more loci and three of these tumours exhibited evidence of 20 or more loci with MI. No correlations were found between MI and previous treatment, site, histological differentiation, positive nodes at pathology, a history of alcohol intake or survival. MI has been demonstrated in T1N0 stage tumours, indicating that these changes may occur early in the disease process. A negative correlation was found between MI and a history of smoking (P = 0.02). Two or more markers of MI were found in three of four non-smokers compared with one of 13 in the smoking group of patients, which suggests a novel mechanism of carcinogenesis in non-smokers.     

Effect of photodynamic therapy in combination with ionizing radiation on human squamous cell carcinoma cell lines of the head and neck

Photodynamic therapy (PDT) is a promising treatment modality for head and neck, and other tumours, using drugs activated by light. A second generation drug, 5-aminolaevulinic acid (5-ALA), is a precursor of the active photosensitizer protoporphyrin IX (PpIX) and has fewer side-effects and much more transient phototoxicity than previous photosensitizers. We have investigated the effect of 5-ALA mediated PDT in combination with gamma-irradiation on the colony forming ability of several human head and neck tumour cell lines. The effect of treatments on the DNA cell cycle kinetics was also investigated. Our results indicate that the combination of 5-ALA mediated PDT and gamma-irradiation results in a level of cytotoxicity which is additive and not synergistic. 5-ALA mediated PDT had no discernible effect on DNA cell cycle distributions. gamma-irradiation-induced cell cycle arrest in G2 did not enhance the phototoxicity of 5-ALA.