Clinicopathologic risk factors for distant metastases from head and neck squamous cell carcinomas

Aims

The aim of this study is to investigate the clinicopathologic risk factors associated with distant metastases (DMs) from head and neck squamous cell carcinomas (HNSCCs).

Methods

Between February 1990 and February 2000, a retrospective analysis of 391 HNSCC patients was performed. The frequency and the clinicopathologic risk factors for DM were evaluated by using univariate χ² tests and multiple stepwise logistic regression models. Statistical analysis of overall survival was performed by using Kaplan–Meier method.

Results

44 patients (11.3%) developed DM in clinic. In a univariate analysis, clinical N stage, primary tumor site, level of tumor invasion, pathologic N stage and number of levels with pathologic lymph node were found to be significantly associated with the risk of DM. In a multivariate analysis, the most significant risk factors were number of levels with pathologic lymph node, level of tumor invasion, and primary tumor site. Kaplan–Meier analysis showed that overall survival rates of 44 patients with DMs in clinic were 56.8% at 1 year, 9.1% at 3 years, and 6.8% at 5 years, respectively.

Conclusions

The number of levels with pathologic lymph node, the site of primary tumor and the level of tumor invasion are decisive risk factors in determining the development of DM in head and neck SCC patients. Patients with multilevel nodal involvement in neck, with laryngeal and hypopharyngeal carcinomas, and patients with primary tumor invasion into muscular, bone or cartilage have the highest risk of developing DM.     

经颞浅动脉灌注PDD-Fudr/5Fu治疗头颈部鳞状细胞癌

 目的　观察经颞浅动脉灌注PDD +Fudr/ 5 Fu治疗头颈部鳞状细胞癌的疗效。方法　从 1996年 1月～ 2 0 0 0年 12月有 89例头颈部鳞状细胞癌给予动脉化疗 ,A组 4 9例予PDD +Fudr方案 ,B组 4 0例予PDD + 5Fu方案 ,方法与剂量两组相同。结果　A组的总有效率为 83.7% (41/ 4 9) ,其中CR10 .2 % ,PR73.5 % ,SD16 .3% ;B组的总有效率为 75 .0 % (30 / 4 0 ) ,其中CR2 .5 % ,PR72 .5 % ,SD2 5 % ,统计学上两组有效率无明显差异 (P >0 .0 5 )。而口腔溃疡在A组的发生率明显低于B组 ,经 χ2 检验 ,两组有显著差异。结论Fudr在头颈部鳞状细胞癌的辅助化疗中是安全、低毒、高效的 ,值得推荐。     

ErbB4 expression in squamous cell carcinoma of the head and neck

This study set out to delineate ErbB4 overexpression and its impact on prognosis in squamous cell carcinoma (SCC) of head and neck (H&N) origin. Thirty-six of the 47 evaluated SCC of H&N origin came from the larynx, oropharynx, or oral cavity. Twenty-four patients had stage III–IV, 17 had stage I–II, and 6 had recurrent disease. Immunohistochemical stains were performed on paraffin sections using the avidin–biotin–peroxidase method. Forty-five patients received radiation therapy, 24 primary treatment and 21 postoperatively. Nineteen patients with advanced stage disease received concomitant chemotherapy. ErbB4 was highly stained in 24/47 (51%) patients and weakly stained in another 13/47 (28%) patients. Age, gender, site, stage, and treatment approaches similarly distributed between the groups. Overall survival (OS) and disease-free survival (DFS) were similar in ErbB4-positive and ErbB4-negative groups. In conclusion, although ErbB4 is not a prognostic parameter for OS and DFS in H&N SCC, it is highly overexpressed. The high overexpression rate may lead to initiation of anti-ErbB4 targeted therapy in this cohort of patients.     

头颈部鳞癌术后辅助放化疗的研究现状

临床研究显示,术后放化疗能够提高头颈部鳞癌术后高危患者的治疗疗效.放疗实施时需根据原发肿瘤部位、临床分期、术后病理和术后影像学评估情况来确定照射靶区和剂量.目前临床上推荐放疗同步应用单药顺铂方案已经达成共识,而放疗同步联合其他化疗药物和(或)表皮生长因子受体(epidermal growth factor receptor,EGFR)单抗的疗效则仍不确定.人乳头状瘤病毒(human papillomavirus,HPV)阳性口咽癌具有独特的生物学特性,其术后放化疗适应证和辅助放化疗的治疗模式至今仍不明确,值得深入研究.     

局部晚期头颈部鳞癌术后辅助治疗的进展

局部晚期头颈部鳞癌的术后辅助治疗在整个治疗中占有重要地位,方案的选择日益注重个体化.调强技术使放疗更精确和适形.术后应尽早开始放疗,超过6周降低局部控制率.综合治疗在11周内完成较好.PET指导勾画靶区的作用仍有待进一步研究和形成共识.术后同步放化疗可以提高高危患者的疗效,但未能明显减少远处转移的发生.分子靶向治疗(西妥昔单抗)的疗效已经在非术后临床试验中被证实.人乳头瘤病毒、表皮生长因子受体和抑癌基因p53是目前分子生物学研究的热点,有望成为寻找个体化治疗新途径的突破口.     

局部晚期头颈部鳞癌同步放化疗研究进展

同步放化疗(CCRT)是治疗局部晚期头颈部鳞癌的新热点。对以手术治疗为主的局部晚期头颈部鳞癌而言,CCRT的疗效与以手术为主的综合治疗的疗效相似,同时保全了器官及功能;对传统采用非手术治疗的局部晚期头颈部鳞癌而言,CCRT取得了更理想的局部控制率、无远处转移率和生存率。因此,CCRT为局部晚期肿瘤的临床治疗提供了新的模式。     

局部晚期头颈部鳞癌同步放化疗研究进展

同步放化疗（CCRT）是治疗局部晚期头颈部鳞癌的新热点。对以手术治疗为主的局部晚期头颈部鳞癌而言，CCRT的疗效与以手术为主的综合治疗的疗效相似，同时保全了器官及功能；对传统采用非手术治疗的局部晚期头颈部鳞癌而言，CCRT取得了更理想的局部控制率、无远处转移率和生存率。因此．CCRT为局部晚期肿瘤的临床治疗提供了新的模式。     

人类乳头状瘤病毒感染与头颈部鳞状细胞癌

大量基础和临床研究的证据显示,人类乳头状瘤病毒(HPV)感染和头颈部鳞状细胞癌(HNSCC)的发生发展有关,但两者间确切发病机制尚不明确.HPV表达E6和E7导致被感染细胞发生恶性转化是其主要的致癌机制.HPV阳性HNSCC对放化疗更为敏感,预后更好.HPV疫苗可能成为预防和治疗HNSCC的重要手段.     

Multiple primary squamous cell carcinomas in the upper digestive tract

Multiple squamous cell carcinomas are common and patients carry a constant and excessive risk of developing a new cancer at any time (13-21 X the normal). Among 6,203 cases of primary squamous carcinoma of the upper digestive tract, 648 patients (10.4%) developed two or more independent tumors. Altogether, 761 additional malignancies were observed, with up to five cancers being seen in individual patients. There were 279 patients with a prior or synchronous cancer and 409 patients who developed 462 metachronous tumors. There was a substantial risk for developing a second primary cancer in the upper aerodigestive tract. Overall the observed to expected ratio was 2.48, specifically 2.32 for males and 2.89 for females.     

Oxygen-modifying treatment with ARCON reduces the prognostic significance of hemoglobin in squamous cell carcinoma of the head and neck

PURPOSE: To evaluate the prognostic significance of hemoglobin (Hb) levels measured before and during treatment with accelerated radiotherapy with carbogen and nicotinamide (ARCON). METHODS AND MATERIALS: Two hundred fifteen patients with locally advanced tumors of the head and neck were included in a phase II trial of ARCON. This treatment regimen combines accelerated radiotherapy for reduction of repopulation with carbogen breathing and nicotinamide to reduce hypoxia. In these patients, Hb levels were measured before, during, and after radiotherapy. RESULTS: Preirradiation and postirradiation Hb levels were available for 206 and 195 patients respectively. Hb levels below normal were most frequently seen among patients with T4 (p < 0.001) and N2 (p < 0.01) disease. Patients with a larynx tumor had significantly higher Hb levels (p < 0.01) than other tumor sites. During radiotherapy, 69 patients experienced a decrease in Hb level. In a multivariate analysis there was no prognostic impact of Hb level on locoregional control, disease-free survival, and overall survival. Primary tumor site was independently prognostic for locoregional control (p = 0.018), and gender was the only prognostic factor for disease-free and overall survival (p < 0.05). High locoregional control rates were obtained for tumors of the larynx (77%) and oropharynx (72%). CONCLUSION: Hemoglobin level was not found to be of prognostic significance for outcome in patients with squamous cell carcinoma of the head and neck after oxygen-modifying treatment with ARCON.     

A novel panel of biomarkers predicts radioresistance in patients with squamous cell carcinoma of the head and neck

PurposeGlobal gene expression analysis was performed on pre-treatment biopsies from patients with squamous cell carcinoma of the head and neck (SCCHN) to discover biomarkers that can predict outcome of radiation based therapy.MethodsWe initially evaluated RNA expression using cDNA microarray analysis of 38 patients that received radiotherapy (RT). The five strongest candidates (VEGF, BCL-2, CLAUDIN-4, YAP-1 and c-MET) were then analysed in pre-treatment biopsies in a second group of 86 patients who received radiation based treatment using immunohistochemical staining (IHC), prepared by tissue microarray.ResultsIn the first population, 13 of 38 (34%) had no (NR) or partial response (PR) to RT. cDNA microarrays revealed 60 genes that were linked to response to therapy. In the second series, 12 of 86 patients (14%) experienced NR or PR to CRT. Cause specific survival (CSS) and recurrence free survival (RFS) at 2 years was 85% and 90% and at 3 years 81% and 84%, respectively. Biomarkers predictive for NR/PR were increased expression of vascular endothelial growth factor (VEGF) (p = 0.02), Yes-associated protein (YAP-1) (p < 0.01), CLAUDIN-4 (p < 0.01), c-MET (p < 0.01) and BCL-2 (p = 0.02). Biomarkers predictive of poor RFS were YAP-1 (p = 0.01) and BCL-2 (p < 0.01). Biomarkers predictive of poor CSS were YAP-1 (p = 0.04), VEGF (p = 0.03) and CLAUDIN-4 (p = 0.03). Furthermore, when YAP-1 and c-MET expression levels were combined the prediction of radio-resistance was increased.ConclusionAll five biomarkers were predictive of poor response to radiation based therapy. In particular, YAP-1 and c-MET have synergistic power and could be used to make treatment decisions.     

Gene expression profiling to predict outcome after chemoradiation in head and neck cancer

PURPOSE: The goal of the present study was to improve prediction of outcome after chemoradiation in advanced head and neck cancer using gene expression analysis. MATERIALS AND METHODS: We collected 92 biopsies from untreated head and neck cancer patients subsequently given cisplatin-based chemoradiation (RADPLAT) for advanced squamous cell carcinomas (HNSCC). After RNA extraction and labeling, we performed dye swap experiments using 35k oligo-microarrays. Supervised analyses were performed to create classifiers to predict locoregional control and disease recurrence. Published gene sets with prognostic value in other studies were also tested. RESULTS: Using supervised classification on the whole series, gene sets separating good and poor outcome could be found for all end points. However, when splitting tumors into training and validation groups, no robust classifiers could be found. Using Gene Set Enrichment analysis, several gene sets were found to be enriched in locoregional recurrences, although with high false-discovery rates. Previously published signatures for radiosensitivity, hypoxia, proliferation, "wound," stem cells, and chromosomal instability were not significantly correlated with outcome. However, a recently published signature for HNSCC defining a "high-risk" group was shown to be predictive for locoregional control in our dataset. CONCLUSION: Gene sets can be found with predictive potential for locoregional control after combined radiation and chemotherapy in HNSCC. How treatment-specific these gene sets are needs further study.     

Cutaneous manifestations associated with malignancy of the head and neck

Most cutaneous malignancies of the head and neck (HN) are non-melanoma skin cancers, predominantly basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). Less common entities include Merkel cell carcinoma (MCC), sebaceous carcinoma (SC), and angiosarcoma. Treatment is based on histology subtype, stage, and extent of involvement. Surgery is the primary means of treatment and includes wide local excision, Mohs micrographic surgery, sentinel lymph node biopsy, and cervical lymphadenectomy. Multidisciplinary management including radiation and targeted chemotherapy are critical adjuncts to surgery. Surgical planning must balance oncologic, functional, and cosmetic considerations. This review addresses cutaneous manifestations of primary malignancies of the HN and dermatologic complications of small molecule inhibitors used for targeted therapy. A working knowledge of both the cutaneous malignancies (CM) in the head and neck as well as the secondary dermatologic manifestations is relevant to multiple disciplines including dermatology, medical oncology, radiation oncology, and surgical oncology.     

Hyperfractionated radiotherapy in advanced squamous cell carcinoma of the head and neck

From January, 1976 to January, 1980, 141 patients (135 males and 6 females) with Stage III and IV squamous cell carcinoma of the head and neck received a split course of hyperfractionated radiotherapy (HFR). In the first group, involving 91 patients, the therapeutic schedule was as follows: first and fourth week, 7.2 Gy per day in 8 sessions of .9 Gy from Monday to Friday, the second and third week no irradiation was given. Thus, patients were given 72 Gy total dose, fractionated into 80 sessions. Mucosal necrosis and severe hemorrhage were responsible for the death of 26 patiens (28%). Therefore the therapeutic protocol was altered for the 50 patients of the second group: during the first and sixth week 6.6 Gy per day in 6 sessions of 1.1 Gy from Monday to Friday. The total dose was thus reduced to 66 Gy fractionated into 60 sessions, resulting in the decrease of toxicity. Regardless of the therapeutic protocol and site of primary, 114 patients (80%) achieved a complete remission and 8 showed a partial remission (>50%), whereas no change was seen for the 19 remainders. Local recurrence appeared in 60 patients (48%). Acute mucositis and laryngeal edema regularly occurred a week after every course of HFR and were considered severe in 40 patients. In spite of toxicity, the median survival is 14 months and 22 patients are still alive in November 1981: 19 without disease, and 8 of these patients have a survival time of at least 3 years.     

Spatial relationship of phosphorylated epidermal growth factor receptor and activated AKT in head and neck squamous cell carcinoma

Background

Overexpression of EGFR correlates with decreased survival after radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the contribution of the activated form, pEGFR, and its downstream signaling (PI3-K/AKT) pathway is not clear yet.

Methods

Fifty-eight patients with HNSCC were included in the study. pEGFR, pAKT, hypoxia, and vessels were visualized using immunohistochemistry. Fractions (defined as the tumor area positive for the respective markers relative to the total tumor area) were calculated by automated image analysis and related to clinical outcome.

Results

Both pEGFR (median 0.6%, range 0-34%) and pAKT (median 1.8%, range 0-16%) expression differed between tumors. Also, a large variation in hypoxia was found (median pimonidazole fraction 3.9% 0-20%). A significant correlation between pEGFR and pAKT (r_s 0.44, p = 0.004) was seen, however, analysis revealed that this was not always based on spatial coexpression. Low pAKT expression was associated with increased risk of regional recurrence (p < 0.05, log-rank) and distant metastasis (p = 0.04).

Conclusion

The correlation between expression of pEGFR and pAKT is indicative of activation of the PI3-K/AKT pathway through phosphorylation of EGFR. Since not all tumors show coexpression to the same extent, other factors must be involved in the activation of this pathway as well.     

System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line

LAT1, a subunit of heterodimeric system L transporter responsible for transporting neutral amino acids into cells, has been investigated in several cancers because of its onco-fetal nature. Based on the studies of its functional inhibition, LAT1 has been proposed to be a new molecular target of a cancer therapy. We have shown here that human head and neck cancer cell line, Hep-2, expresses both LAT1 and 4F2hc, another subunit of system L transporter. An inhibitor of system L, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), inhibited leucine uptake by the cells. BCH administration or restriction of essential amino acid leucine decreased viability of Hep-2 cells. Co-administration of cisplatin with BCH reduced the viability of the cells more than either agent alone. When BCH treatment preceded cisplatin administration, reduction in Hep-2 cell viability was additive. In contrast, when BCH was given after cisplatin treatment, synergistic effect in decreasing the number of viable cells was obtained. BCH treatment decreased the phosphorylation of mTOR, p70S6K and 4EBP1, suggesting that BCH enhanced anti-tumor action of cisplatin by inhibiting mTOR pathway. This potentiation may be used to reduce cisplatin exposure to alleviate many unwanted toxicity of the drug.     

Postoperative radiotherapy for head and neck squamous cell carcinomas: Feasibility of a biphasic accelerated treatment schedule

: It has been suggested that postoperative tumor cell proliferation may influence the outcome of advanced head and neck squamous cell carcinomas treated by surgery and postoperative radiotherapy. This Phase I pilot study was undertaken to determine the feasibility of a biphasic accelerated radiotherapy regimen with early and late concomitant boost delivery for postoperative treatment of patients with advanced head and neck cancers.

: From April 1993 to April 1994, 29 patients with advanced head and neck cancers were enrolled in this study after they underwent complete surgical resection. The basic radiation course delivered a median dose of 49 Gy in 25 fractions over 5 weeks at 1.8–2 Gy/fraction. The concomitant boost was delivered to the high-risk areas as a second daily fraction during the first (1.4 Gy/fraction) and fifth weeks (1.6 Gy/fraction). The total dose to the high-risk areas was 64 Gy in 35 fractions over 5 weeks.

: Twenty-seven patients (93%) completed the treatment without interruptions. Only two patients experienced severe acute toxicity requiring treatment breaks of 6 and 8 days, respectively. All patients developed confluent mucositis; in 69% of the cases it covered >50% of the treated surface. No patient developed Grade 5 (ulceration/bleeding) mucosal reaction. Mucositis required a median time of 7 weeks for complete healing (range 3–43. Two patients developed transient bone exposure. The median weight loss was 5.5% of pretreatment body weight (range 1.2–17.1%), and four patients required nutritional with nasogastric feeding tube.

: The results of this study show that this biphasic acceleration regimen is feasible with acceptable acute toxicity.