The national landscape of human papillomavirus‐associated oropharynx squamous cell carcinoma

The head and neck squamous cell carcinoma (HNC) landscape is evolving with human papillomavirus (HPV) being a rising cause of oropharynx carcinoma (OPC). This study seeks to investigate a national database for HPV‐associated oropharynx carcinoma (HPV‐OPC). Using the National Cancer Data Base, we analyzed 22,693 patients with HPV‐OPC and known HPV status. Chi‐square tests and logistic regression models were utilized to examine differences between HPV positive and HPV negative OPC. 14,805 (65.2%) patients were HPV positive. Mean age at presentation was 58.4 years with HPV‐HNC patients being 2.8 years younger compared to the HPV‐negative cohort (58.4 vs. 61.2 years, p < 0.001). 67.6% of white patients were HPV‐positive compared to 42.3% of African American patients and 57.1% of Hispanics (p < 0.001). When combining race and socioeconomic status (SES), we found African American patients in high SES groups had HPV‐OPC prevalence that was significantly higher than African American patients in low SES groups (56.9% vs. 36.3%, p < 0.001). Geographic distribution of HPV‐OPC was also analyzed and found to be most prevalent in Western states and least prevalent in the Southern states (p < 0.001). The distribution of HPV‐OPC is variable across the country and among racial and socioeconomic groups. A broad understanding of these differences in HPV‐OPC should drive educational programs and improve clinical trials that benefit both prevention and current treatments.     

Cathepsin D in tissue and serum of patients with squamous cell carcinoma of the head and neck

Aspartic proteinase cathepsin D (CD) is believed to be associated with proteolytic processes leading to local invasion and seeding of tumour cells. To estimate a potential prognostic value of cathepsin D in squamous cell carcinoma of the head and neck, its total concentration was measured immunoradiometrically (ELSA-CATH-D kit, CIS bio international) in cytosols of tumour and adjacent normal tissue samples from 111 patients; in 42/111 patients, the CD concentration was determined in serum samples obtained at diagnosis (serum no. 1) and after the therapy (serum no. 2) from each of these patients. Sera of 15 healthy volunteers served as controls. A significantly elevated concentration of CD was measured in tumour cytosols as compared to normal tissue cytosols (31.1 versus 12.6 pmol/mgp, P<0.0001) and in cytosols of normal laryngeal tissue than of the oral cavity or pharynx (13.3 versus 11.2 pmol/mgp, P=0.03). The higher CD tumour concentration correlated with the age of the patients (≤60 versus >60 years, 28.8 versus 32.8 pmol/mgp, P=0.045) and histopathological tumour grade (G₁₊₂ versus G₃, 32.6 versus 24.4 pmol/mgp, P=0.02). In serum samples, a lower concentration of CD was measured in the control group than in the patients (3.6 versus 4.1 pmol/mls, P=0.045) and in serum no. 1 than in serum no. 2 (4.1 versus 5.1 pmol/mls, P=0.05). The CD concentration in sera obtained at diagnosis was stage-dependent (S_I–III versus S_IV, 3.9 versus 4.7 pmol/mls, P=0.09); there was a trend towards lower CD concentrations with an increasing time delay in serum no. 2 sampling (R_S=−0.20, P=0.21). No correlation was observed between cytosolic and serum concentrations of CD. We conclude that our results confirm a specific role of CD in the process of invasion and metastasis of squamous cell carcinoma of the head and neck, which might also be of prognostic value in this particular cancer type.     

Modifying effect of MDM4 variants on risk of HPV16-associated squamous cell carcinoma of oropharynx

BACKGROUND:

The p53 pathway plays a critical role in maintaining genomic stability and preventing tumor formation. Given the roles of both MDM4 and HPV16 E6 oncoproteins in inhibition of p53 activity, we tested the hypothesis that MDM4 polymorphisms are associated with the risk of HPV16‐associated squamous cell carcinoma of head and neck (SCCHN).

METHODS:

Genotyping was conducted on 3 tagging single nucleotide polymorphisms (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) in MDM4, and serology was used to determine HPV 16 exposure in 380 cases and 335 cancer‐free controls that were frequency‐matched by age, sex, smoking, and drinking status.

RESULTS:

None of 3 MDM4 polymorphisms alone was significantly associated with risk of overall SCCHN. With further analysis stratified by HPV16 serology and tumor site, we found that each polymorphism individually modified the risk of HPV16‐associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly pronounced in never smokers and never drinkers.

CONCLUSION:

The risk of HPV16‐associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings. Cancer 2011;. © 2011 American Cancer Society.     

Gefitinib,Methotrexate and Methotrexate plus 5-Fluorouracil as palliative treatment in recurrent head and neck squamous cell carcinoma

This study compared the efficacy and toxicity of Gefitinib, Methotrexate and Methotrexate plus 5-Fluorouracil (5-FU) in patients of recurrent squamous cell carcinoma of head and neck (SCCHN) treated with palliative intent. Patients with recurrent SCCHN not amenable to curative treatment were randomly assigned to Gefitinib, Methotrexate or Methotrexate plus 5-FU arm. The primary end point was overall survival. Secondary end points of interest were objective response rate, toxicity and quality of life. Total 117 patients were analyzed. Median overall survival and objective response rates were 8.8 months, 7.8 months and 8.1 months and 7.7%, 5.0% and 7.9% in Gefitinib, Methotrexate and Methotrexate plus 5-FU arms respectively with no statistically significant difference between 3 arms. Gefitinib had different toxicity profile compared with other arms. Majority of toxicities were Grade 1 or Grade 2. Gefitinib had significant improvement in quality of life during initial months over Methotrexate. There was no suggestion that Gefitinib significantly prolonged overall survival compared with Methotrexate and Methotrexate plus 5-FU. However, improved Quality of Life with manageable toxicities was observed.     

Adjuvant radiotherapy improves overall survival for patients with lymph node-positive head and neck squamous cell carcinoma

BACKGROUND: Although adjuvant radiotherapy (RT) is often recommended for locally advanced squamous cell carcinoma of the head and neck (HNSCC), its effect on overall or cancer-specific survival has not been clearly demonstrated. In the current study, the frequency and effect of adjuvant RT on overall survival was investigated in patients with resected lymph node-positive head and neck cancer. METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database, patients were selected with lymph node-positive HNSCC (American Joint Committee on Cancer and SEER stage 3/4) who were treated either with surgery alone or surgery and RT and were diagnosed between 1988 and 2001. A total of 8795 patients who met the inclusion criteria for analysis comprised the study population, with a median follow-up of 4.3 years for patients still alive at the time of last follow-up. RESULTS: Adjuvant RT was utilized in 84% of patients. Adjuvant RT improved the 5-year overall survival (43.2% [95% confidence interval (95% CI), 41.9-44.4%] for surgery + RT vs 33.4% [95% CI, 30.7-36.0%] for surgery alone; P < .001) and cancer-specific survival (50.9% for surgery + RT vs 42.1% for surgery) on univariate analysis. On multivariate analysis, adjuvant RT (hazards ratio [HR] of 0.78; 95% CI, 0.71-0.86 [P < .001]) remained a significant predictor of improved survival. The significant benefit of radiation on overall survival was noted for lymph node-positive patients with both primary tumors localized to the involved organ (HR of 0.81; 95% CI, 0.71-0.94 [P = .007]) and more locally invasive primary tumors (HR of 0.77; 95% CI, 0.68-0.87 [P < .001]). CONCLUSIONS: In what to the authors' knowledge is the largest reported analysis of adjuvant RT in patients with locally advanced HNSCC published to date, adjuvant RT resulted in an approximately 10% absolute increase in 5-year cancer-specific survival and overall survival for patients with lymph node-positive HNSCC compared with surgery alone. Despite combined surgery and adjuvant RT, outcomes in this high-risk population remain suboptimal, emphasizing the need for continued investigation of innovative treatment approaches.     

Estimating the risks and benefits before salvage surgery for recurrent head and neck squamous cell carcinoma

IntroductionThe risks associated with salvage surgery of head and neck squamous cell carcinoma (SCC) in a previously irradiated field needs to be balanced against the expected survival benefits. We want to identify preoperative predictive factors for overall and disease-specific survival (OS/DSS) and for the development of serious (Clavien-Dindo, CD≥III) complications following salvage surgery for radiorecurrent SCC to help surgeons, patients, and caregivers in the decision-making process in this setting.Materials and methodsThe records of 234 patients presenting to the Lorraine Cancer Institute with locoregional radiorecurrent SCC were reviewed. The primary endpoint was OS, secondary endpoints were DSS, OS without tracheostomy/gastrostomy, and the risk of CD≥III complications. Multivariate analyses were carried out to explore preoperative factors associated with survival and the risk of postoperative complications.ResultsWith a median follow-up time of 19 months, 5-year OS since the first salvage surgery was 28.3%, 5-year DSS was 38.9%. 2- and 5-year functional OS were 45.6% and 27.2%. rcT-rcN, and WUNHCI ≥4 were both independent significant preoperative predictors of OS and DSS. 30-days postoperative complications occurred in 44.4% of patients (28 CD I, 24 CD II, 34 CD III, 11 CD IV, 7 CD V). A salvage procedure involving T+N plus the presence of a WUHNCI ≥4 was the only independent predictor of CD≥III complications.ConclusionWhen discussing with the patients and the caregivers salvage surgery for recurrent head and neck SCC, a careful evaluation of the preoperative comorbidities by the WUHNCI tool can reliably predict the expected risks and benefits from the procedure.     

Conditional survival in head and neck squamous cell carcinoma: results from the SEER dataset 1973-1998

BACKGROUND: Survival statistics for patients with head and neck squamous cell carcinomas (HNSCC) are commonly calculated from the time of diagnosis. The less commonly employed conditional survival (CS) analyzes survival for patients who have survived a period of time after diagnosis. Useful prognostic information for cancer survivors is provided by CS analysis. Estimated baseline CS parameters for HNSCC were sought using large-scale cancer registry data. METHODS: HNSCC cases identified from the Surveillance, Epidemiology, and End Results (SEER) Program were accessed to identify those diagnosed between 1973 and 1998. Five-year observed, relative, and cumulative CS calculations were performed, with secondary stratification by site, extent of disease, and age. RESULTS: The overall 5-year observed survival for all sites increased from 47.8% for 76,181 included patients from the time of diagnosis to 64.4% for those 43,985 patients alive at 3 years, and thereafter plateaus. The greatest increase in CS was for oropharyngeal cancers, which more than doubled over the first decade of surveillance (26.5%-60%). Distant disease showed a 10-year increase in CS (17.4%-60.4%), whereas localized disease CS was essentially static, ranging from 66.1% to 68.5%; for those over 65 at diagnosis it ranged from 39.9-52.9%, whereas patients <65 years at diagnosis ranged from 53.8-73.5%. CONCLUSIONS: Benchmark CS estimates for domestic HNSCC cohorts were developed from the SEER database. CS is a useful tool to assist clinicians in predicting the probability of demise from HNSCC for patients surviving 1 or more year after diagnosis.     

Single-agent docetaxel in patients with platinum-refractory metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN)

BACKGROUND: The objective of this retrospective study was to investigate the efficacy and tolerability of single-agent docetaxel in patients with platinum-refractory squamous cell carcinoma of the head and neck (SCCHN). METHODS: Platinum-refractory disease was defined as cancer with documented tumor progression during platinum-based treatment or recurrence within 6 months after platinum-based chemoradiotherapy. Patients fulfilling the following criteria were enrolled: histologically confirmed SCCHN, excluding nasopharyngeal cancer; measurable metastatic lesions as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST); and platinum-refractory disease. Docetaxel (60 mg/m2) was administered every 3-4 weeks and continued unless there was evidence of disease progression or unacceptable toxicity. RESULTS: Twenty patients were recruited. Overall response rate was 10% (2/20) and tumor control rate was 25% (5/20). Median progression-free and median overall survival times were 1.7 and 4.6 months, respectively. The most common hematological toxicities were leucopenia (grade 4: 35%) and neutropenia (grade 4: 30%). Grade 3 febrile neutropenia and grade 3 mucositis (functional/symptomatic) each occurred in two patients (10%). One fatal bleeding occurred during this treatment, however, the relation between this event and docetaxel was unlikely. Median inpatient period during treatment was 5.4 days (range, 0-50 days). CONCLUSION: A single-agent docetaxel regimen appeared to offer an acceptable clinical profile in patients with platinum-refractory SCCHN.     

Loss of MTBP expression is associated with reduced survival in a biomarker-defined subset of patients with squamous cell carcinoma of the head and neck

BACKGROUND:

Recent genetic studies have implicated p53 mutation as a significant risk factor for therapeutic failure in squamous cell carcinoma of the head and neck (SCCHN). However, in a recent meta‐analysis in the literature of p53 from major anatomical subsites (larynx, oral cavity, oropharynx/hypopharynx), associations between patient survival and p53 status were ambiguous.

METHODS:

The authors examined a cohort of SCCHNs using a previously developed biomarker combination that likely predicts p53 status based on p53/MDM2 expression levels determined by immunohistochemistry (IHC). In addition, the authors generated and validated an antibody to MTBP (an MDM2 binding protein that alters p53/MDM2 homeostasis and may contribute to metastatic suppression) and have incorporated data for MTBP expression into the current analyses.

RESULTS:

Analysis of expression data for p53 and MDM2 in 198 SCCHN patient samples revealed that the biomarker combination p53 + ve/MDM2‐low (likely indicative of p53 mutation) was significantly associated with reduced overall survival (log‐rank P = .035) and was an independent prognostic factor (P = .013; HR, 1.705; 95% CI, 1.12‐2.60); thus, these data were compatible with earlier genetic analyses. By using IHC for p53 and MDM2 to dichotomize patients, the authors found that loss of MTBP expression was significantly associated with reduced survival (log‐rank P = .004) and was an independent prognostic factor (P = .004; HR, 2.78; 95% CI, 1.39‐5.54) in p53 + ve/MDM2‐low patients.

CONCLUSIONS:

These results represent the first examination of MTBP expression in human tissues and provide evidence for a p53 status‐dependent role for MTBP in suppressing disease progression in SCCHN patients as well as confirming a role for p53 pathway function in delaying disease progression. Cancer 2011. © 2011 American Cancer Society.     

Role of miRNA in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Evidence suggests that miRNAs play an important role in progression, recurrence, metastasis and postoperative survival of HNSCC. Studies have investigated the utility of miRNAs as diagnostic/prognostic tools and as potential therapeutic targets and biomarkers that may improve the management and outcomes of HNSCC. The aim of this article is to review the current literature on aberrant expression profiles of miRNAs in biopsy samples of HNSCC and their role in cancer development, metastasis, prognosis and survival of these patients. This review gives an overview that miRNAs deregulation play major role in the development of HNSCC. They offer the potential to be used as biomarkers or novel therapeutic targets. Future research is required to test their use in both of these fields.     

中性粒细胞/淋巴细胞比值对舌鳞状细胞癌患者预后的预测价值

目的 舌鳞状细胞癌(tongue squamous cell carcinoma,TSCC)是最常见的头颈部肿瘤之一,其生长较局限,早期易发生淋巴结转移.本研究探讨术前外周血中性粒细胞/淋巴细胞比值(neutrophil-to-lymphocyte ratio,NLR)对TSCC患者预后的评估价值.方法 回顾性分析广州医科大学附属肿瘤医院2011-01-01-2014-12-31行根治性手术治疗的56例TSCC患者临床资料,根据患者术前外周血NLR分为低NLR组(NLR≤1.94,28例)和高NLR组(NLR＞1.94,28例),分析两组患者NLR与临床病理因素之间的关系,比较两组患者的总生存率(overall survival,OS)和无瘤生存率(disease-free survival,DFS).结果 NLR升高与患者年龄、性别、不良嗜好、肿瘤生长部位、临床分期、复发无显著相关(P＞0.05),而与肿瘤分化程度(P=0.003)、淋巴结转移(P=0.035)密切相关;低NLR组患者的1、3、5年OS分别为96.4％、85.7％和85.7％,高NLR组分别为78.6％、57.1％和53.6％;两组5年DFS分别为82.1％和39.3％,差异有统计学意义,P＜0.05.单因素回归分析显示,肿瘤中低分化、肿瘤临床分期(Ⅲ～Ⅳ期)、复发和术前NLR(NLR＞1.94)与患者OS、DFS相关,是患者预后不良的影响因素;多因素Cox回归分析显示,肿瘤中低分化、肿瘤临床分期(Ⅲ～Ⅳ期)、复发术前NLR(NLR＞ 1.94)是影响患者总生存期的独立预后因素.结论 术前高NLR(NLR＞ 1.94)是影响TSCC患者预后的独立危险因素,术前NLR升高提示TSCC患者预后不良.     

The usefulness of pretreatment DNCB in 85 patients with squamous cell carcinoma of the upper aerodigestive tract

Pretreatment DNCB skin testing and absolute lymphocyte counts were studied in 85 consecutive head and neck cancer patients. All patients were treated primarily with radiation therapy alone or combined radiation plus surgery. The results of DNCB testing and absolute lymphocyte counts were not sufficiently predictive of outcome, (no evidence of disease after 2 years) to be useful in making treatment decisions on an individual patient. This applied to the good prognosis (T1, T2, N0-N3) and poor prognosis (T3, T4, N0-N3) groups.     

Radiotherapy or surgery for head and neck squamous cell cancer

BACKGROUND:

The authors compared the survival outcomes of radiotherapy +/? salvage surgery to surgery +/? postoperative radiotherapy for patients with squamous cell cancer of the hypopharynx. There was no evidence beyond observational studies and no consensus on the which treatment is most effective for this patient group.

METHODS:

The authors conducted a retrospective population‐based study of 595 patients from Ontario Canada diagnosed between January 1, 1990 and December 31, 1999. Three different methodological approaches were used for the survival analysis including a restricted cohort study, a matched case‐control study, and a natural experiment study across defined geographic regions.

RESULTS:

The authors found no survival advantage for either radiotherapy +/? salvage surgery or surgery +/? postoperative radiotherapy.

CONCLUSIONS:

This study set the baseline for clinical decisions that was not previously established there is no difference in survival for patients with hypopharynx comparing primary surgery to primary radiotherapy. This information is essential for the interpretation of current treatment results, the planning of future clinical studies and the treatment of patients who are not having chemoradiotherapy. Cancer 2009. © 2009 American Cancer Society.     

Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data.

BACKGROUND: Radiotherapy (RT) with concurrent chemotherapy is the current standard of care for patients with unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN). Gemcitabine (GEM) is a potent radiosensitizer and in addition has activity as an anticancer agent in SCCHN. PATIENTS AND METHODS: Twenty-six patients with locally far advanced SCCHN were enrolled in a chemoradiation feasibility study between November 1998 and September 2003. Use was made of conventionally fractionated RT and GEM 100 mg/m(2), which was given within 2 h prior to radiotherapy on a weekly basis starting on day 1 of RT. Response was assessed according to WHO criteria, toxicity according to NCI-CTC version 2. RESULTS: The patients received a median of 7 (2-8) weekly cycles of gemcitabine and a median cumulative RT dose of 70 Gy (66-84.75). Hematologic toxicity was mild, but non-hematologic toxicity was severe: grade 3-4 stomatitis occurred in 85% of patients, dermatitis in 69%, pharyngitis/esophagitis in 81% and 80% of the patients needed a feeding tube during treatment. All 22 evaluable patients responded (50% complete, 50% partial). Median follow up of the surviving patients is 46 months. Median disease-free and overall survival is 13 months and 19 months, respectively; 27% of the patients are alive without evidence of recurrence beyond 3 years. CONCLUSIONS: Conventionally fractionated RT in combination with GEM 100 mg/m(2) weekly is feasible and highly active in the treatment of locally advanced SCCHN. In particular, long-term local control rate is promising. Acute mucosal toxicities are significant but manageable. Long-term toxicity interferes with normal food intake.