Smoking-related Malignancies Research Articles

Thyroid cancer and multiple primary tumors in the SEER cancer registries1

Thyroid cancer incidence rates have increased steadily in the United States and elsewhere. Radiation exposure at a young age is a strong risk factor, but otherwise the etiology is unclear. To explore etiologic clues, we studied the risk of thyroid cancer after an earlier primary cancer, as well as the risk of developing multiple primaries after an earlier thyroid cancer in the U.S. Surveillance, Epidemiology and End-Results (SEER) cancer registries program (1973-2000). In 2,036,597 patients diagnosed with any invasive cancer who survived for a minimum of 2 months, we observed a 42% increased risk compared to the general population for second thyroid cancer based on 1,366 cases (95% confidence interval (CI) = 35-50%; excess absolute risk (EAR) = 0.38/10,000 person-years (PY)). Elevated risks were observed after most cancer sites studied. The most pronounced excess (observed/expected (O/E) = 2.86) was seen for second thyroid cancers detected in the year after diagnosis of the first cancer. Among 29,456 2-month thyroid cancer survivors, 2,214 second cancers occurred (O/E = 1.11, 95% CI = 1.06-1.15; EAR = 7.64/10,000 PY). Again, the highest risk was seen in the first year (O/E = 1.26). Patients <40 years of age at diagnosis of thyroid cancer had a 39% increased risk of a second cancer, whereas for older patients the risk was elevated 6%. We observed consistently increased risks for cancers of the breast, prostate, and kidney, and a likely radiation treatment-related excess of leukemia. Based on small numbers of cases, cancers of the salivary glands, trachea, scrotum, adrenal glands, and brain and central nervous system (CNS) also occurred in excess. A decreased risk was observed for smoking-related malignancies. Thyroid cancer is associated with primary cancers of many different organs. Although enhanced medical surveillance likely plays a role, 2-way, positive associations between thyroid cancer and cancers of the breast, prostate, kidney, salivary glands, brain and CNS, scrotum, and leukemia suggest etiologic similarities and possible treatment effects.

Cancer incidence in parents who lost a child: a nationwide study in Denmark.

It has been debated whether psychological stress causes cancer, but the scientific evidence remains contradictory. The objective of this study was to investigate whether the death of a child is related to cancer risk in bereaved parents. The authors undertook a follow-up study based on national registers. All 21,062 parents who lost a child from 1980 to 1996 were recruited for the exposed cohort together with 293,745 randomly selected, unexposed parents. Cox proportional hazards regression models were used to evaluate the relative risk of cancer incidence up to 18 years after the bereavement. The main outcomes of interest were all incident cancers, breast carcinoma, smoking-related malignancies (International Classification of Diseases [ICD] 7 codes 140, 141, 143-149, 150, 157, 160-162, 180, and 181), alcohol-related malignancies (ICD7 codes 141, 143-146, 148-150, 155, and 161), virus/immune-related malignancies (ICD7 codes 155, 171, 191, 200-202, and 204), lymphatic/hematopoietic malignancies (ICD7 codes 200-205), and hormone related malignancies (ICD7 codes 170, 172, 175, and 177). The authors observed a slightly increased overall cancer risk in bereaved mothers (relative risk [RR], 1.18; 95% confidence interval [95%CI], 1.01-1.37; P = 0.028) at 7-18 years of follow-up. There was an increased risk for smoking-related malignancies (RR, 1.65; 95%CI, 1.05-2.59; P = 0.010) among bereaved mothers during the 7-18 years of follow-up. The authors observed no significantly increased relative risk of breast carcinoma, alcohol-related malignancies, virus/immune-related malignancies, or hormone-related malignancies. The current data suggest that the death of a child was associated with a slightly increased overall cancer risk in mothers and that the increase may be related to stress-induced adverse life styles.

Book of the Month: Snake Oil and Other Preoccupations

Book of the Month: Snake Oil and Other Preoccupations

Long-term prognosis after partial gastrectomy for gastroduodenal ulcer.

The decline in duodenal ulcer disease and the established relation of peptic ulcer to Helicobacter pylori have virtually abolished the need for elective ulcer surgery. However, a substantial proportion of the population around retirement age has previously been subjected to partial gastric resection due to peptic ulcer, and the long-term outcome of these patients is of continuing relevance. Patients subjected to elective surgery could represent a selected group of healthy subjects with a lower overall morbidity, but reports indicate that patients operated on for peptic ulcer have more advanced disease associated with excess smoking and a different pattern of social behavior. The surgical procedure induces enterogastric reflux, leading to profound changes in the remnant mucosa and the formation of carcinogens in the gastric juice. In addition, metabolic abnormalities are common, especially fat malabsorption. Evaluation of the impact of these factors on morbidity and mortality is difficult. Increased mortality in gastrointestinal tumors (especially gastric stump carcinoma), respiratory diseases and other smoking-related malignancies, and suicide are found in the long-term follow-up after partial gastric resection due to peptic ulcer. However, these hazards to life are offset by a decreased mortality in cardiovascular disease. Preventive measures against suicide and especially tobacco smoking are recommended to improve th outcome for this cohort.

Smoking and Risk of Non-Hodgkin Lymphoma Subtypes in a Cohort of Older Women

Although non-Hodgkin lymphoma (NHL) has not been considered to be a smoking-related malignancy, recent investigations suggest otherwise. We evaluated this association in a cohort of 37,336 women, aged 55-69 years, who reported in a mailed questionnaire in 1986 information regarding smoking history as well as demographic, medical history and dietary factors. Cancer and mortality experience through 1996 was determined by linkage to the Iowa Cancer Registry and other databases; there were 200 incident cases of NHL during the 380231 total person-years of follow-up. Compared to never smokers, former (age-adjusted RR = 1.0; 95% CI 0.8-1.5) and current smokers (age-adjusted RR = 1.0; 95% CI 0.7-1.5) were not at elevated risk of NHL, and there was no trend with pack-years smoked (ptrend = 0-3)- Multivariate adjustment for other NHL risk factors did not alter these findings. Age-adjusted analysis by NHL subtype revealed a suggestive positive association of smoking with follicular NHL (RRformer= 1.3; 95% CI 0.6-2.8), (RRcurrent = 1.8; 95% CI 0.8-3.8)], which strengthened after multivariate adjustment [(RRformer = 1.6; 95% CI 0.7-3.4), (RRcurrent = 2.3; 95% CI 1.0-5.0)]; there was no association for diffuse or small cleaved-cell NHL. Our study findings, which are consistent with other recent investigations, suggest that smoking may be associated with an increased risk of follicular NHL.

Dose-Intensive Therapy in Small Cell Lung Cancer

Basic to curative treatment for small cell lung cancer (SCLC) are the principles of dose response, combination chemotherapy, and combined-modality therapy. Theory and experimental and clinical data suggest that solid tumors recur, despite initially responding to chemotherapy due to drug resistance. Resistance to chemotherapy is potentially overcome by using 5- to 10-fold higher doses. To decrease the emergence of drug resistance, combinations of active non-cross-resistant agents are used. Hematopoietic stem cell support provides the opportunity to test dose response to the limits of organ tolerance. Dose-intensive therapy for lung cancer patients is complicated by the fact that this disease most often occurs in an older-aged population (median, 60 to 65 years) with underlying smoking-related comorbid disease, early metastatic spread, and enhanced risk of secondary smoking-related malignancies. In a phase II feasibility trial just activated, patients younger than 60 years of age with limited-stage SCLC are being treated with four cycles of cisplatin and etoposide and concurrent twice-daily chest radiotherapy to 45 Gy (150-cGy fractions). Those patients achieving complete or near-complete response will receive high-dose cyclophosphamide/cisplatin/ carmustine with autologous stem cell support. Upon recovery, prophylactic cranial irradiation will be given. Results could lead to a phase III trial testing the concept of dose intensification. This article reviews evidence for the contribution of dose intensification to response and survival in the treatment of SCLC, the adequacy of the clinical trial's design to address these relationships, and suggestions for future directions. The strategies of dose-intensive induction therapy, multicycle dose-intensive combination therapies, chest radiography, and stem cell purging trials will be discussed.

Dose-intensive therapy in lung cancer.

Lung cancer is epidemic and lethal throughout the world. Overall survival is estimated to be 13% at 5 years despite treatment. The use of chemotherapy in small-cell lung cancer (SCLC) is established, but it is less active against non-SCLC (NSCLC). Since 98% of SCLC cases are associated with heavy smoking and present at a median age of 60-65 years, the application of dose-intensive therapy to lung cancer patients may be complicated by underlying smoking-related comorbidity and an enhanced risk for secondary smoking-related malignancies. The strategies of intensifying induction therapy, multicycle dose-intensive combination therapies, chest radiotherapy, and stem cell purging for both SCLC and NSCLC are discussed herein. Limited data regarding high-dose therapy for NSCLC have been reported. In SCLC, excellent and immediate palliation is achieved through the use of combination chemotherapy. However, by 2 years, only 20-40% of limited-disease-(LD) and < 5% of extensive-disease stage (ED) patients remain alive. Regimens developed using the many established agents produce similar short- and long-term outcomes, an observation that suggests that many of our systemic agents eradicate the same tumor subpopulation but fail to abolish a central core of tumor stem cells, presumably enriched for heterogeneous in vivo resistance mechanisms. The identification of these minimal residual tumor (MRT) cells and systematic evaluation of their biologic characteristics may guide strategies to target these cells specifically; such strategies may include modification of chemotherapy, tumor vaccination, or other forms of biologic therapy, such as replacement of RB, 3p, and/or p53 function; interference with autocrine or paracrine growth loops; or immunologic therapy [interleukin (IL)-2, IL-12, immunotoxins, and tumor vaccines], which would be most effective in the setting of MRT. To this end the detection of heterogeneity and analysis of patterns of coexpression of various markers form the thrust of our MRT detection program. At the Dana-Farber Cancer Institute and Beth Israel Hospital we performed stem-cell autografts in > 40 patients with LD SCLC and > 25 patients with ED SCLC who were in first response to conventional-dose therapy comprising high-dose combination alkylating agents. Approximately 80% of our patients were in or near complete response after initial chemotherapy. At a minimal follow-up of 23 months (to as long as 10 years) after completion of high-dose chemotherapy in our original trial, 52% of the patients remain disease-free. Of the ED or extrapulmonary patients, approximately 20% remain progression-free at > 2 years after high-dose therapy. Local regional recurrence represents about 50% of all relapses. Thus, the roles of thoracic radiation dose intensity and purification of stem-cell autografts are being evaluated in ongoing trials. It is hoped that a cooperative phase III trial testing the concept of dose intensification will begin soon.

Correlation analysis of alveolar macrophage cytochemical parameters in smoking and pulmonary oncology.

Cytochemical examination of alveolar macrophages (AM) obtained by bronchoalveolar lavage (BAL) was performed in healthy volunteers (11 non-smokers and 11 smokers) and in 9 patients with squamous lung carcinoma (all of them smokers or ex-smokers) in order to analyze its peculiarities related to the smoking habit and to lung malignancy. Assessment of non-specific esterases: alpha-naphthyl acetate esterase (ANAE) and butyrate esterase (BUT), chloroacetate esterase (CHL), acid phosphatase (AcP), intracellular glycogen (PAS reaction), lipids (Sudan black B reaction-SBB) and iron (Perl's reaction) was performed by a semiquantitative cytochemical method (1). A significant correlation was obtained between BUT and stage of squamous lung carcinoma (varying between I and IV) (r = 0.52, p < 0.05). There was a correlation between BUT and Perl's in healthy controls (r = 0.76, p < 0.05). The same type of correlation was observed in control smokers (r = 0.64, p < 0.05), in addition to a correlation between CHL and AcP (r = 0.69, p < 0.05). There was no significant BUT/Perl's correlation in patients with squamous cell lung carcinoma (r = 0.23, p > 0.05), but significant AcP/CHL correlation as was observed in control smokers (r = 0.73, p < 0.05), and a "new" type of correlation was shown to exist between ANAE and SBB (r = 0.77, p < 0.05). In spite of the unresolved nature of lung cancer, correlation analysis of cytochemical parameters in AM might have an important part in the analysis of their relative contribution to the development of smoking-related disorders and lung malignancies.

Mutagen Sensitivity as a Risk Factor for Second Malignant Tumors Following Malignancies of the Upper Aerodigestive Tract

Second malignant tumors in patients successfully treated for an initial cancer of the upper aerodigestive tract are an important cause of morbidity and mortality. Biologic markers capable of identifying high-risk subgroups of patients who could be targeted for intensive clinical surveillance, therefore, have immense therapeutic and prognostic relevance. We previously demonstrated in a pilot study of 84 patients with cancers of the upper aerodigestive tract that mutagen sensitivity was a significant predictor of risk of developing second malignant tumors. We extended the study to include 278 patients diagnosed with previously untreated cancers of the upper aerodigestive tract from 1987 to August 1993. For each patient, base-line (pretreatment) mutagen sensitivity was measured in vitro in 50 metaphases established from peripheral lymphocyte cultures. Patients with an average of more than 1 chromosomal break/cell were deemed mutagen hypersensitive. Cox proportional hazards analysis was used to predict the risk of developing second malignant tumors associated with mutagen sensitivity. Overall, 44% of the case group exhibited mutagen hypersensitivity. There were no differences in the distribution of mutagen hypersensitivity by site, sex, stage of disease, or smoking status. There were 17 synchronous and 11 metachronous cancers, of which 15 (54%) were smoking-related malignancies. Sixteen (13.1%) of the mutagen-sensitive patients developed second malignant tumors, compared with 12 (7.7%) of the nonsensitive patients. The mean break/cell value (+/- SD) for patients developing second malignant tumors was 1.17 (+/- 0.54), compared with 0.98 (+/- 0.44) for patients with only one cancer (P = .04). Mutagen hypersensitivity conferred a relative risk of 2.67 (95% confidence interval = 1.22-5.79) of developing second malignant tumors. Mutagen hypersensitivity increases the risk of developing second malignant tumors. Future research should focus on the molecular mechanisms underlying mutagen sensitivity.

Second Malignancy in Stomach Cancer Patients and Its Possible Risk Factors

To identify possible risk factors of multiple primary cancers in stomach cancer patients, a case-control analysis based on data from medical records was conducted on 73 patients (54 males and 19 females) with stomach cancer who were affected by one or more other primary cancers subsequently or concurrently (cases) and 146 patients with stomach cancer alone (controls), by matching sex, age, time of the operation for stomach cancer and survival period. The relative risks (RR) for cancer history in the father (RR = 3.21), for family history of stomach cancer (RR = 2.52) and for history of hemorrhoids (RR = 3.15) were significantly increased in both sexes. The proportion of professionals in males was significantly higher in cases than in controls. In a conditional multiple logistic regression analysis for males, the adjusted relative risk (aRR) for family history of cancer in two or more members (aRR = 3.54) was statistically significant. Smoking tended to increase the risk of multiple primary cancers in males, especially in the cases with smoking-related second malignancy (RR = 4.83). These data suggest the possibility that both genetic and environmental factors are involved in the multiplicity of cancer in stomach cancer patients.

Distribution and reproducibility of aryl hydrocarbon hydroxylase inducibility in a prospective population study of middle-aged male smokers and nonsmokers.

Aryl hydrocarbon hydroxylase (AHH) inducibility was determined in a lymphoblast test system in 2,000 consecutive middle-aged male smokers, 304 ex-smokers, and 218 never-smokers in the same birth-year cohorts. Intraindividual, intraobserver, and interobserver, as well as temporal, reproducibility was checked in a special double-blind quadruplet sample series from 20 other consecutive middle-aged men. The results showed a three-modal phenotype distribution of AHH inducibility with high (fold induction greater than or equal to 3.6), intermediate (2.6-3.6) and low (less than or equal to 2.5) levels ranging between 7.6% to 10.5%, 38.5% to 43.0%, and 46.5% to 53.9%, respectively, in all the smoking categories. The reproducibility of the measurements was excellent, with one-way variance in the order of 0.007 to 0.033, and the applied assay method can therefore be used in large-scale prospective population investigations. Such are required in order to establish a cause-effect association between high AHH inducibility and smoking-related malignancies of the respiratory tract and oral cavity, as has been suggested from earlier retrospective studies in more limited clinical materials of cancers and precanceroses of these varieties.