Allelic loss in esophageal squamous cell carcinoma patients with and without family history of upper gastrointestinal tract cancer.

Chromosomal regions with frequent allelic loss may point to major susceptibility genes that will assist in understanding molecular events involved in esophageal carcinogenesis. Esophageal squamous cell carcinoma samples and blood from 46 patients, including 23 patients with and 23 patients without a family history of upper gastrointestinal cancer, were screened using laser microdissected DNA and tested for loss of heterozygosity (LOH) at 18 marker loci representing 14 chromosomal regions (on 2q, 3p, 4p, 4p, 5q, 6q, 8p, 9p, 9q, 11p, 13q, 14q, 15q, and 17p) identified in an earlier genome-wide scan to have frequent LOH. Clinical/pathological and lifestyle risk factor data were also collected. For all 46 tumors combined, the lowest frequency LOH for any of the 18 markers was 37%, and 8 markers showed LOH in > or =75% of informative tumors. One marker (D13S894 on 13q) showed greater LOH in patients with a positive family history (93% versus 50%; P = 0.04), whereas two markers (D6S1027 on 6q and D9S910 on 9q) had significantly more LOH in patients with metastasis, and one marker (D4S2361 on 4p) showed significantly higher LOH in patients with a lower pathological tumor grade. No relation was seen between LOH and lifestyle risk factors. This study confirms the previously observed high frequency LOH for these 14 chromosomal regions, including a locus on 13q where LOH is more common in patients with a family history of upper gastrointestinal cancer than in those without such history, suggesting that a gene in this area may be involved in genetic susceptibility to esophageal cancer.     

Socioeconomic factors associated with risk of upper aerodigestive tract cancer in Europe

IntroductionIn the European Union, there are 180,000 new cases of upper aerodigestive tract (UADT) cancer cases per year – more than half of whom will die of the disease. Socioeconomic inequalities in UADT cancer incidence are recognised across Europe. We aimed to assess the components of socioeconomic risk both independently and through their influence on the known behavioural risk factors of smoking, alcohol consumption and diet.Patients and methodsA multicentre case–control study with 2198 cases of UADT cancer and 2141 controls from hospital and population sources was undertaken involving 14 centres from 10 countries. Personal interviews collected information on demographics, lifetime occupation history, smoking, alcohol consumption and diet. Socioeconomic status was measured by education, occupational social class and unemployment. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using unconditional logistic regression.ResultsWhen controlling for age, sex and centre significantly increased risks for UADT cancer were observed for those with low versus high educational attainment OR = 1.98 (95% CI 1.67, 2.36). Similarly, for occupational socioeconomic indicators – comparing the lowest versus highest International Socio-Economic Index (ISEI) quartile for the longest occupation gave OR = 1.60 (1.28, 2.00); and for unemployment OR = 1.64 (1.24, 2.17). Statistical significance remained for low education when adjusting for smoking, alcohol and diet behaviours OR = 1.29 (1.06, 1.57) in the multivariate analysis. Inequalities were observed only among men but not among women and were greater among those in the British Isles and Eastern European countries than in Southern and Central/Northern European countries. Associations were broadly consistent for subsite and source of controls (hospital and community).ConclusionSocioeconomic inequalities for UADT cancers are only observed among men and are not totally explained by smoking, alcohol drinking and diet.     

Cancer screening of upper aerodigestive tract in Japanese alcoholics with reference to drinking and smoking habits and aldehyde dehydrogenase-2 genotype

In this study, 1,000 Japanese male alcoholics were consecutively screened by upper gastrointestinal endoscopy with esophageal iodine staining. Associations among cancer-detection rates, drinking and smoking habits, and aldehyde dehydrogenase-2 (ALDH2) genotypes were evaluated. A total of 53 patients (5.3%) had histologically confirmed cancer. Esophageal cancer was diagnosed in 36, gastric cancer in 17, and oropharyngolaryngeal cancer in 9 patients: 8 of the esophageal-cancer patients were multiple-cancer patients, with additional cancer(s) in the stomach and/or oropharyngolaryngeal region. Multiple logistic regression revealed that use of stronger alcoholic beverages (whisky or shochu) in contrast with lighter beverages (sake or beer) and smoking of 50 pack-years or more increased the risks for esophageal (odds ratio 3.2 and 2.8 respectively), oropharyngolaryngeal (4.8 and 5.1 respectively) and multiple cancer (10.5 and 11.8 respectively). The inactive form of ALDH2, encoded by the gene ALDH2^*1/2^*2 prevalent in Orientals, exposes them to higher blood levels of acetaldehyde, a recognized animal carcinogen, after drinking. This inactive ALDH2 was detected in 19/36 (52.8%) patients with esophageal cancer, in 5/9 (55.6%) patients with oropharyngolaryngeal cancer, and in 7/8 (87.5%) patients with multiple cancer. All of these gene frequencies far exceeded that in a large alcoholic cohort (80/655, 12.2%). The triple combination of the risk factors of the inactive ALDH2, stronger alcoholic beverages and heavy smoking was more commonly associated with multiple-cancer patients than with patients with esophageal cancer alone (62.5% vs. 7.1%). These results show that the 3 risk factors are important for the development of upper-aerodigestive-tract cancer in Japanese alcoholics. For these high-risk drinkers, regimented screening appears to be indicated. © 1996 Wiley-Liss, Inc.     

Coffee and green tea consumption is associated with upper aerodigestive tract cancer in Japan

The impact of coffee and green tea consumption on upper aerodigestive tract (UADT) cancer risk has not been established. Evaluation of the possible anticarcinogenic properties of their ingredients is confounded by the potential increase in risk owing to the high temperatures at which these beverages are generally consumed. We conducted a case–control study to evaluate the association between coffee and tea consumption and the risk of UADT cancer. The study enrolled 961 patients with UADT cancer and 2,883 noncancer outpatients who visited Aichi Cancer Center between 2001 and 2005. Information on coffee and green tea consumption and other lifestyle factors was collected via a self‐administered questionnaire. Consumption of three or more cups of coffee per day had a significant inverse association with UADT cancer [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.55–0.96]. In contrast, consumption of three or more cups of green tea per day had a significant positive association with UADT cancer (OR 1.39, 95% CI 1.13–1.70). These associations were evident for head and neck cancer but not for esophageal cancer. The association of coffee consumption with head and neck cancer was observed only among never smokers and alcohol drinkers. Similarly, the association of green tea consumption was observed among never smokers and never alcohol drinkers. No change in these associations was seen on stratification by each confounding factors. These findings suggest that consumption of coffee might be associated with a decreased risk of UADT cancer, whereas that of green tea might be associated with an increased risk.     

Diet,alcohol, smoking and cancer of the upper aerodigestive tract: A prospective study among Hawaii Japanese men

A cohort study of upper aerodigestive tract cancer was conducted among 7,995 Japanese—American men who were interviewed and examined from 1965 to 1968. Information was collected about smoking history and alcohol and dietary intake. After 24 years, 92 incident cases with histological confirmation of diagnosis were identified. Current cigarette smokers at time of examination had a 3-fold risk for upper aerodigestive tract cancer compared with never-smokers. A dose-response relationship was present with increasing amount and duration of cigarette use. Consumption of beer, wine, spirits and total alcohol was strongly associated with increased risk. Of 23 food and beverage categories, only candy/jelly/soda pop consumption had a statistically significant inverse trend. Frequent consumption of fruit was also inversely associated with this cancer. In contrast, the risk tended to be positively associated with consumption of rice, seaweed, tofu or tsukudani (a mixed dish of fish, sugar, soy sauce and seaweed), but the dose—response relationship was not statistically significant. For nutrient intake, increased calcium and fat intake decreased the risk for this cancer.     

Oral health,dental care and mouthwash associated with upper aerodigestive tract cancer risk in Europe: The ARCAGE study

ObjectiveWe aimed to assess the association of oral health (OH), dental care (DC) and mouthwash with upper-aerodigestive tract (UADT) cancer risk, and to examine the extent that enzymes involved in the metabolism of alcohol modify the effect of mouthwash.Materials and methodsThe study included 1963 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1993 controls. Subjects were interviewed about their oral health and dental care behaviors (which were converted to scores of OH and DC respectively), as well as smoking, alcohol drinking, diet, occupations, medical conditions and socio-economic status. Blood samples were taken for genetic analyses. Mouthwash use was analyzed in relation to the presence of polymorphisms of alcohol-metabolizing genes known to be associated with UADT. Adjusted odds ratios (ORs) and 95%-confidence intervals [CI] were estimated with multiple logistic regression models adjusting for multiple confounders.ResultsFully adjusted ORs of low versus high scores of DC and OH were 2.36[CI = 1.51–3.67] and 2.22[CI = 1.45–3.41], respectively, for all UADT sites combined. The OR for frequent use of mouthwash use (3 or more times/day) was 3.23[CI = 1.68–6.19]. The OR for the rare variant ADH7 (coding for fast ethanol metabolism) was lower in mouthwash-users (OR = 0.53[CI = 0.35–0.81]) as compared to never-users (OR = 0.97[CI = 0.73–1.29]) indicating effect modification (p_{heterogeneity} = 0.065) while no relevant differences were observed between users and non-users for the variant alleles of ADH1B, ADH1C or ALDH2.ConclusionsPoor OH and DC seem to be independent risk factors for UADT because corresponding risk estimates remain substantially elevated after detailed adjustment for multiple confounders. Whether mouthwash use may entail some risk through the alcohol content in most formulations on the market remains to be fully clarified.     

Conformal radiotherapy in cancer of the upper aerodigestive tract]

The outcome of head and neck malignancies is closely related to the achievement of local tumor control. The occurrence of severe late complications is the consequence of the anatomic vicinity between dose-limiting normal tissues and the tumor, thus reducing the curative potential of radiotherapy. Conformal radiotherapy is presently actively investigated as a way to improve the dose distribution in head and neck malignancies (especially when originating from the nasopharynx or the sinuses) while protecting healthy organs. Such an approach requires a chain of sophisticated procedures, including efficient quality assurance programs, in order to achieve the proper degree of safety. The relatively limited clinical studies published to-date have already confirmed the advantage of conformal radiotherapy in terms of dose delivery. The development of beam intensity modulation is likely to further contribute to the improvement of the therapeutic ratio.     

Occupation and risk of upper aerodigestive tract cancer: the ARCAGE study

We investigated the association between occupational history and upper aerodigestive tract (UADT) cancer risk in the ARCAGE European case-control study. The study included 1,851 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1,949 controls. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ever employment in 283 occupations and 172 industries, adjusting for smoking and alcohol. Men (1,457 cases) and women (394 cases) were analyzed separately and we incorporated a semi-Bayes adjustment approach for multiple comparisons. Among men, we found increased risks for occupational categories previously reported to be associated with at least one type of UADT cancer, including painters (OR = 1.74, 95% CI: 1.01-3.00), bricklayers (1.58, 1.05-2.37), workers employed in the erection of roofs and frames (2.62, 1.08-6.36), reinforced concreters (3.46, 1.11-10.8), dockers (2.91, 1.05-8.05) and workers employed in the construction of roads (3.03, 1.23-7.46), general construction of buildings (1.44, 1.12-1.85) and cargo handling (2.60, 1.17-5.75). With the exception of the first three categories, risks both increased when restricting to long duration of employment and remained elevated after semi-Bayes adjustment. Increased risks were also found for loggers (3.56, 1.20-10.5) and cattle and dairy farming (3.60, 1.15-11.2). Among women, there was no clear evidence of increased risks of UADT cancer in association with occupations or industrial activities. This study provides evidence of an association between some occupational categories and UADT cancer risk among men. The most consistent findings, also supported by previous studies, were obtained for specific workers employed in the construction industry.     

Intraoperative radiation therapy in the multimodality approach to upper aerodigestive tract cancer

The cure rate of operable lung cancer and locally advanced head and neck cancer remains suboptimal, with a limited rate of local control despite improvements in the surgical removal of primary tumors and in methods for mediastinal lymph node dissection, in particular. The efficacy of adjuvant therapy, such as EBRT, has improved, and the immediate efficacy of new chemotherapeutic drugs is increasingly significant, although local recurrences remain frequent. Locoregional failure is not uncommon in upper aerodigestive tract cancers. Factors limiting radiocurability for locally advanced (stage III) lung cancer include mediastinal intolerance of irradiation (high risk of mediastinal fibrosis, which increases exponentially when levels of much more than 50 Gy are administered to the whole mediastinum) and the very high radiosensitivity of the healthy lung, which can develop fibrosis with relatively small or moderate doses starting at 18 to 20 Gy, and even more frequently when larger volumes are irradiated. Head and neck neoplasms are less difficult sites in which to administer doses of up to 70 Gy of external beam radiotherapy initially, but, like locoregionally recurrent lung cancers, they are not easily reirradiated with tumoricidal doses of EBRT. For these reasons, IORT seems to be a good option for increasing local control, because areas of [figure: see text] residual microscopic disease may be irradiated using IOERT approaches without affecting critical organs to the same extent. In addition, careful patient selection is paramount. Combined modality treatment regimens incorporating IORT may benefit patients with locally advanced disease. The ability of IORT to sterilize microscopic residual disease can enhance the "completeness" of resection and thus, theoretically, improve local control. Although distant disease dissemination remains by far the overriding issue, as newer effective agents emerge, local failure will continue to be a problem. Preliminary studies have demonstrated that IORT can be administered to patients who have locally advanced NSCLC and head and neck cancer, in the context of aggressive combined modality therapy, and is generally well tolerated. Long-term efficacy and benefit can only be determined in the setting of carefully designed clinical trials. (See the article by Thomas and Merrick elsewhere in this issue for further discussion of this topic.) Several relatively small, single-institution pilot studies exploring the utility and benefit of IORT for locally advanced upper aerodigestive tract cancers have been conducted. Clear conclusions have been difficult to determine because of the mixing of disease stages, varying degrees and completeness of surgical resection, varying radiation doses, different schemas, and other factors. Yet, given the major morbidity and mortality associated with locally recurrent lung cancer, methods of improving local control need to be pursued and refined. Encouraging preliminary data suggest that IOERT can be safely administered and may benefit local control. Based on several centers' expertise in the combined modality treatment of locally advanced lung cancer and familiarity with IORT, the UCSF Thoracic Oncology Program has proposed a multicenter phase 2 study incorporating IORT in a combined multimodality treatment schema for patients who have completely resected locally advanced stage IIIA and IIIB NSCLC (nonpleural effusion, non-N3) (Fig. 1). It is hoped that this study will commence in the upcoming year.     

Cigarette smoking patterns in patients after treatment of upper aerodigestive tract cancers

There is a paucity of data on variables predictive of successful smoking cessation in cancer patients. In this questionnaire-based study, we report the smoking status of 75 patients (46 men, 29 women) with head and neck cancer followed for a minimum of 30 months after definitive therapy. Seventy-one percent of the men and 61% of the women who were current smokers at diagnosis stopped smoking subsequent to diagnosis and treatment. Only 29% and 39%, respectively, continued to smoke, most at decreased intensity. Patients with laryngeal cancer were most likely to have stopped (83%). Conversely, patients with oral cavity cancer were most likely to be continuing smokers (66%). In addition, older age, college education, and lighter smoking habits were somewhat predictive of successful cessation. Fear of recurrent disease and physician advice were the questionnaire-listed incentives most often chosen as contributing to success in cessation. The role health professionals can play in counseling cancer patients to stop smoking is stressed.     

Family aggregation of carcinoma of the hypopharynx and cervical esophagus: Special reference to multiplicity of cancer in upper aerodigestive tract

The role of family history in the multiple occurrence of cancer in the upper aerodigestive tract (UADT) remains unclear. The family histories of close relatives were examined in 167 patients with either hypopharyngeal or cervical esophageal cancer (PhCe cancer) and in 167 control subjects with benign diseases. The odds ratio for PhCe cancer was 2.6 in relation to family history of UADT cancers. Based on the family histories of close relatives, 167 cases with PhCe cancer were divided into 3 groups (Group I, 18 cases with a family history of UADT cancer; Group II, 37 cases with a family history of other cancers; Group III, 112 cases with no family history of any cancers). The mean age of the cases in group I was 59.4, which was younger than in group III (64.2). Second primary squamous-cell carcinomas in the UADT were more frequently recognized in group I (39%) than in group III (11%). However, no differences were observed in the smoking and drinking habits of male patients between each group. These results thus suggest that a family history of UADT cancers appears to be associated with the multiple occurrence of UADT cancers as well as the development of PhCe cancer. Int. J. Cancer 76:468-471, 1998.© 1998 Wiley-Liss, Inc.     

侵犯上呼吸消化道的高分化甲状腺癌的治疗

目的：探讨侵犯上呼吸消化道的高分化甲状腺癌的治疗方式。方法：回顾性分析62例侵犯上呼吸消化道的高分化甲状腺癌的治疗方法。全组均行手术治疗,术式以肿瘤削除术为主,17例患者术后行放射性碘治疗,3例行术后放疗。全部病例随访2～15年。结果：肿瘤局限性侵犯患者,手术削除干净无残留者5年局部控制率达100．0％(17／17);肿瘤广泛侵犯突入腔内而行扩大切除者为87．5％(7／8);局限性侵犯、手术削除不干净有残留者为55．6％(5／9)。姑息性切除疗效最差。17例少量肿瘤残留者术后行放射性碘治疗,其5年局部控制率与未作此治疗者,差异有显著性。结论：对于侵犯上呼吸消化道的高分化甲状腺癌,应根据具体情况选择合适的术式;对有少量肿瘤残留者术后应辅以同位素治疗,病程较晚期者宜行术后放疗。     

Squamous cell carcinoma of the upper aerodigestive tract in nonusers of tobacco

Nine hundred forty-five patients with squamous cell carcinoma of the upper aerodigestive tract (SCC-UADT) were treated at three University of Louisville-affiliated hospitals from 1970 through 1979. Retrospective analysis disclosed that 33 patients (3.4%) never used tobacco. This group offers interesting contrasts to the more prevalent tobacco-related epidermoid cancers. Cancers in nonusers of tobacco (mean age, 68 years) occurred approximately 10 years later than most epidermoid UADT cancers. Women predominated with a ratio of 2.7 to 1. Fifteen of 16 patients (94%) older than 70 years were women. Twenty-four of 33 primary lesions (72%) were in the oral cavity and two thirds of these were staged 0, I, and II (American Joint Commission [AJC]). Of the patients younger than 70 years of age, 42% were men, 42% had non-oral primaries, and most (74%) had advanced disease in AJC Stages III and IV. Second squamous cell primaries of the UADT developed in 6 of the 33 patients (18%) with an average of 48 disease-free months. Five of six were oral lesions in patients with original oral primaries. Of the 16 patients older than 70 years with small, localized oral cancers, conservative surgery failed in 9 (56%). Although 4 were salvaged by re-excision or radiation, 5 of these 16 patients in AJC Stage 0, I, and II died of this cancer (32%). The tendency for conservative initial surgical treatment in older patients is believed to be responsible for the higher than expected rate of treatment failure. An aggressive approach is recommended and further supported by the complete absence of surgical mortality in this group of patients.     

Risk of metachronous squamous cell carcinoma in the upper aerodigestive tract of Japanese alcoholic men with esophageal squamous cell carcinoma: a long-term endoscopic follow-up study

East Asian case–control studies have shown a strong relationship between alcohol consumption combined with inactive heterozygous aldehyde dehydrogenase-2 ( ALDH2 * 1/ * 2 ) and the development of squamous cell carcinoma (SCC), especially multiple SCC, of the upper aerodigestive tract (UADT). This study aimed to identify determinants of the development of metachronous SCC in the UADT in alcoholics with esophageal SCC. Follow-up endoscopic examinations were carried out 4–160 months (median, 41 months) after initial diagnosis in 110 Japanese alcoholic men with esophageal SCC diagnosed by screening using endoscopy combined with oropharyngolaryngeal inspection and esophageal iodine staining. ALDH2 * 1/ * 2 was significantly associated with the presence of multiple primary intraesophageal SCC at the time of initial diagnosis. Metachronous primary SCC of the esophagus was diagnosed in 29 of the 81 patients whose initial esophageal SCC was treated by endoscopic mucosal resection alone, and metachronous primary SCC of the oropharyngolarynx was diagnosed in 23 of the 99 patients without synchronous primary SCC of the oropharyngolarynx at the time of initial diagnosis. The risks of metachronous esophageal SCC and oropharyngolaryngeal SCC were significantly higher in ALDH2 * 1/ * 2 heterozygotes than in ALDH2 * 1/ * 1 homozygotes (age-adjusted and alcohol-adjusted hazard ratio = 3.38 [95% confidence interval: 1.45–7.85] and 4.27 [1.42–12.89], respectively), and in patients with multiple intraesophageal SCC at the time of initial diagnosis than in patients with a solitary intraesophageal SCC (3.09 [1.41–6.78] and 3.25 [1.41–7.47], respectively). ALDH2 * 1/ * 2 and multiple synchronous intraesophageal SCC were found to be predictors of metachronous SCC in the UADT in this population. ( Cancer Sci 2008; 99: 1164–1171)     

Tomatoes, tomato-rich foods, lycopene and cancer of the upper aerodigestive tract: a case-control in Uruguay

In order to study the relationship between tomatoes, tomato products, lycopene and cancers of the upper aerodigestive tract (UADC; oral cavity, pharynx, larynx, esophagus) a case-control study was carried out in Uruguay, in the time period 1996-98. Two-hundred and thirty eight cases and 491 hospitalized controls were frequency matched on age, sex, residence and urban/rural status. Both series were submitted to a detailed questionnaire, including tobacco smoking, alcohol drinking and queries on 64 food items. These data were analyzed by unconditional logistic regression, after adjusting by total energy intake. Tomato intake was associated with a reduction in risk of 0.30 (95% confidence interval [CI], 0.18-0.51), whereas tomato sauce-rich foods displayed a protective effect of 0.57 (95% CI, 0.33-0.96 for the highest quartile of intake). The food group composed of raw tomato and tomato-rich foods showed a strong inverse association with UADC (odds ratio [OR], 0.23; 95% CI, 0.13-0.39 for the highest quartile of intake). Lycopene was also strongly associated with a reduced risk of 0.22 (95% CI, 0.13-0.37). Adjustment of tomato intake for several phytochemicals explained almost completely its protective effect, which disappears in this model. Finally, the joint effect of lycopene and total phytosterols was associated with a significant reduction in risk (OR, 0.11; 95% CI, 0.05-0.23).