Luigi Barzan

Sentinel Node Biopsy in Head and Neck Cancer: Preliminary Results of a Multicenter Trial

Background: The aim was to determine the reliability and reproducibility of sentinel node biopsy (SNB) as a staging tool in head and neck squamous cell carcinoma (HNSCC) for T1/2 clinically N0 patients by means of a standardized technique.Methods: Between June 1998 and June 2002, 227 SNB procedures have been performed in HNSCC cases at six centers. One hundred thirty-four T1/2 tumors of the oral cavity/oropharynx in clinically N0 patients were investigated with preoperative lymphoscintigraphy (LSG), intraoperative use of blue dye/gamma probe, and pathological evaluation with step serial sectioning and immunohistochemistry, with a follow-up of at least 12 months. In 79 cases SNB alone was used to stage the neck carcinoma, and in 55 cases SNB was used in combination with an elective neck dissection (END).Results: In 125/134 cases (93%) a sentinel node was identified. Of 59 positive nodes, 57 were identified with the intraoperative gamma probe and 44 with blue dye. Upstaging of disease occurred in 42/125 cases (34%): with hematoxylin-eosin in 32/125 (26%) and with additional pathological staging in 10/93 (11%). The sensitivity of the technique with a mean follow-up of 24 months was 42/45 (93%). The identification of SNB for floor of mouth (FOM) tumors was 37/43 (86%), compared with 88/91 (97%) for other tumors. The sensitivity for FOM tumors was 12/15 (80%), compared with 30/30 (100%) for other tumor groups.Conclusion: SNB can be successfully applied to early T1/2 tumors of the oral cavity/oropharynx in a standardized fashion by centers worldwide. For the majority of these tumors the SNB technique can be used alone as a staging tool.

Food groups, oils and butter, and cancer of the oral cavity and pharynx

SummaryTo elucidate the role of dietary habits, a study was carried out in 1992–1997 in the province of Pordenone in Northeastern Italy, and those of Rome and Latina in central Italy. Cases were 512 men and 86 women with cancer of the oral cavity and pharynx (lip, salivary glands and nasopharynx excluded) and controls were 1008 men and 483 women who had been admitted to local hospitals for a broad range of acute non-neoplastic conditions. The validated dietary section of the questionnaire included 78 foods or recipes and ten questions on fat intake patterns. After allowance for education, smoking, alcohol and total energy intake, significant trends of increasing risk with increasing intake emerged for soups, eggs, processed meats, cakes and desserts, and butter. Risk was approximately halved in the highest compared to the lowest intake quintile for coffee and tea, white bread, poultry, fish, raw and cooked vegetables, citrus fruit, and olive oil. The inverse association with oils, especially olive oil, was only slightly attenuated by allowance for vegetable intake. Thus, frequent consumption of vegetables, citrus fruit, fish and vegetable oils were the major features of a low-risk diet for cancer of the oral cavity and pharynx.

Combined effect of tobacco and alcohol on laryngeal cancer risk: a case-control study

Objective: To provide information on the effects of alcohol and tobacco on laryngeal cancer and its subsites. Methods: This was a case–control study conducted between 1992 and 2000 in northern Italy and Switzerland. A total of 527 cases of incident squamous-cell carcinoma of the larynx and 1297 hospital controls frequency-matched with cases on age, sex, and area of residence were included. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using multiple logistic regression. Results: In comparison with never smokers, ORs were 19.8 for current smokers and 7.0 for ex-smokers. The risk increased in relation to the number of cigarettes (OR = 42.9 for ≥25 cigarettes/day) and for duration of smoking (OR = 37.2 for ≥40 years). For alcohol, the risk increased in relation to number of drinks (OR = 5.9 for ≥56 drinks per week). Combined alcohol and tobacco consumption showed a multiplicative (OR = 177) rather than an additive risk. For current smokers and current drinkers the risk was higher for supraglottis (ORs 54.9 and 2.6, respectively) than for glottis (ORs 7.4 and 1.8) and others subsites (ORs 10.9 and 1.9). Conclusions: Our study shows that both cigarette smoking and alcohol drinking are independent risk factors for laryngeal cancer. Heavy consumption of alcohol and cigarettes determined a multiplicative risk increase, possibly suggesting biological synergy.

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10−10 and 10−9, respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.

Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals

BACKGROUND Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens. METHODS We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies. RESULTS Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96-1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23-1.38, P = 1 x 10(-18)), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19-1.35, P = 5 x 10(-13)). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01-1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour. CONCLUSIONS This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.

Comparison of the effect of smoking and alcohol drinking between oral and pharyngeal cancer.

To compare the separate and combined effects of alcohol drinking and smoking between the 2 sites, we evaluated 274 men with oral cancer, 364 with pharyngeal cancer and 1,254 controls, frequency‐matched for age and area of residence, from Italy and Switzerland. Extremely elevated risk increases for oral cancer (odds ratio, OR = 228) and pharyngeal cancer (OR = 100) were found for the highest joint level of drinking (≥77 drinks/week) and smoking (≥25 cigarettes/day). Ratios of ORs between oral cancer and pharyngeal cancer vs. controls, obtained by polytomous logistic regression, suggested that the risk increase for oral cancer was about 2‐fold greater than that for pharyngeal cancer at each combined level of smoking and drinking, except at low levels of drinking in smokers. A clear departure from risk difference additivity was present for both oral and pharyngeal cancer in individuals heavily exposed to both factors versus non‐smoking abstainers/light drinkers. Our findings thus help explain observations from descriptive epidemiology that, if smoking level in a population does not change substantially, but alcohol consumption increases, increase in oral cancer would be greater than at any other site in the upper aero‐digestive tract, including cancer of the pharynx. Int. J. Cancer 83: 1–4, 1999.

Population attributable risk of tobacco and alcohol for upper aerodigestive tract cancer.

Tobacco and alcohol are major risk factors for upper aerodigestive tract (UADT) cancer and significant variation is observed in UADT cancer rates across Europe. We have estimated the proportion of UADT cancer burden explained by tobacco and alcohol and how this varies with the incidence rates across Europe, cancer sub-site, gender and age. This should help estimate the minimum residual burden of other risk factors to UADT cancer, including human papillomavirus. We analysed 1981 UADT cancer cases and 1993 controls from the ARCAGE multicentre study. We estimated the population attributable risk (PAR) of tobacco alone, alcohol alone and their joint effect. Tobacco and alcohol together explained 73% of UADT cancer burden of which nearly 29% was explained by smoking alone, less than 1% due to alcohol on its own and 44% by the joint effect of tobacco and alcohol. Tobacco and alcohol together explained a larger proportion of hypopharyngeal/laryngeal cancer (PAR=85%) than oropharyngeal (PAR=74%), esophageal (PAR=67%) and oral cancer (PAR=61%). Tobacco and alcohol together explain only about half of the total UADT cancer burden among women. Geographically, tobacco and alcohol explained a larger proportion of UADT cancer in central (PAR=84%) than southern (PAR=72%) and western Europe (PAR=67%). While the majority of the UADT cancers in Europe are due to tobacco or the joint effect of tobacco and alcohol, our results support a significant role for other risk factors in particular, for oral and oropharyngeal cancers and also for UADT cancers in southern and western Europe.

Radiotherapy for patients with early-stage glottic carcinoma : univariate and multivariate analyses in a group of consecutive, unselected patients

Radiotherapy (RT) has a remarkable success rate in the treatment of patients with glottic carcinoma. The objectives of the current study were to assess the results in a group of consecutive patients with comparable characteristics who were treated with RT (6‐megavolt photon linear accelerator) and to determine the prognostic factors that may influence local control in patients with early‐stage glottic carcinoma. The impact on local control of tobacco smoking and second primary malignancies also was investigated.

Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 european countries: The ARCAGE project

Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus and account for 6.4% of all new cancers in Europe. In the context of a multicenter case-control study conducted in 14 centers within 10 European countries and comprising 1,511 cases and 1,457 controls (ARCAGE study), 115 single nucleotide polymorphisms (SNP) from 62 a priori-selected genes were studied in relation to UADT cancer. We found 11 SNPs that were statistically associated with UADT cancers overall (5.75 expected). Considering the possibility of false-positive results, we focused on SNPs in CYP2A6, MDM2, tumor necrosis factor (TNF), and gene amplified in squamous cell carcinoma 1 (GASC1), for which low P values for trend (P trend<0.01) were observed in the main effects analyses of UADT cancer overall or by subsite. The rare variant of CYP2A6 -47A>C (rs28399433), a phase I metabolism gene, was associated with reduced UADT cancer risk (P trend=0.01). Three SNPs in the MDM2 gene, involved in cell cycle control, were associated with UADT cancer. MDM2 IVS5+1285A>G (rs3730536) showed a strong codominant effect (P trend=0.007). The rare variants of two SNPs in the TNF gene were associated with a decreased risk; for TNF IVS1+123G>A (rs1800610), the P trend was 0.007. Variants in two SNPs of GASC1 were found to be strongly associated with increased UADT cancer risk (for both, P trend=0.008). This study is the largest genetic epidemiologic study on UADT cancers in Europe. Our analysis points to potentially relevant genes in various pathways.

Flavonoids and the Risk of Oral and Pharyngeal Cancer: A Case-Control Study from Italy

The intake of flavonoids has been inversely related to the risk of various common neoplasms, but scanty data exist on oral and pharyngeal cancer. We used data from a case-control study conducted in Italy between 1992 and 2005 to examine the relationship between flavonoid intake and oral and pharyngeal cancer risk. The study included 805 cases with incident, histologically confirmed oral and pharyngeal cancer, and 2,081 hospital controls admitted for acute, nonneoplastic conditions. We have applied data on food and beverage content of six major classes of flavonoids, on dietary information collected through a validated food-frequency questionnaire. The odds ratios (OR) were calculated using multiple logistic regression models, conditioned on study center, sex, and age. After adjustment for education, tobacco, alcohol, body mass index, and non–alcohol energy intake, ORs for the highest versus the lowest quintile of intake were 0.51 [95% confidence intervals (95% CI), 0.37-0.71] for flavanones, 0.62 (CI, 0.43-0.89) for flavonols, and 0.56 (95% CI, 0.40-0.78) for total flavonoids. No significant association emerged for isoflavones (OR, 0.90), anthocyanidins (OR, 0.86), flavan-3-ols (OR, 0.84), and flavones (OR, 0.75). The ORs were consistent across strata of age, sex, education, body mass index, tobacco, and alcohol. After allowance for vegetable and fruit consumption, the inverse relations with total flavonoids and flavanones remained significant, whereas that with flavonols became nonsignificant. None of the associations were significant after further allowance for vitamin C, probably on account of the high collinearity between these compounds. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1621–5)