ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.

OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. CONCLUSION: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Variation in the use of chemotherapy in lung cancer.

Factors influencing the use of chemotherapy for the initial (6 months) treatment of lung cancer in South East England were investigated. The variables explored as possibly influencing the use of chemotherapy were sex, age, the year of diagnosis, the type of lung cancer, the stage, the index of multiple deprivation and the cancer network of residence. Chi2 analysis and multivariate logistic regression models were used to examine the effect of each of the variables on the use of chemotherapy. The results showed a highly significant trend in use of chemotherapy over time; the adjusted proportion of patients receiving chemotherapy increasing from 13.6% in 1994 to 29.3% in 2003. However, age, cancer network and type of lung cancer had the strongest influence on the use of chemotherapy. This finding is important when we consider that the NHS Cancer Plan aims at improving inequalities in cancer care in the UK.

Review of thyroid cancer cases among patients with previous benign thyroid disorders.

A previous register linkage study showed an increased risk of thyroid cancer among patients previously discharged from a hospital with a diagnosis of a benign thyroid disorder. In this study, we have reviewed all available medical records, first to validate the earlier result and second to describe the symptomatology of patients with a history of benign thyroid disorder prior to the cancer diagnosis. The previous study identified 189 patients with a benign and subsequent malignant thyroid disorder. Medical records were obtainable for 156 of these patients and were reviewed. For 104 patients, benign and malignant thyroid diseases were metachronous (a clearly separated disease history of the benign and malignant diseases), and for 48 patients synchronous. In 4 cases, thyroid cancer could not be confirmed. Among patients with metachronous thyroid disorders, all major benign thyroid disorders were represented including hot nodules, diffuse and multinodular toxic and nontoxic goiter. Symptoms preceding diagnosis of thyroid cancer included growth of goiter/nodules, globulus, stridor, hoarseness, and metastasis. No major differences were found among patients with metachronous and synchronous benign and malignant thyroid disorder, apart from the fact that all metastases were found among metachronous cases. This study confirmed the conclusion that patients with a previous history of goiter or nodules have an increased risk of thyroid cancer. However, thyroid cancer still occurs too infrequently to warrant screening in all patients with a previous history of goiter or nodules.

Cancer risk in individuals with benign thyroid disorders.

The risk of cancer was examined in a cohort of 57,326 individuals who were discharged from a Danish hospital with a diagnosis of myxedema, thyrotoxicosis, or goiter. Although the general risk of cancer was only slightly increased, the risk of several sites was significantly above expected. The risk of thyroid cancer especially, was increased with standardized incidence ratios among women of 2.1 (myxedema), 2.5 (thyrotoxicosis), and 6.6 (nontoxic goiter). The increase in risk was present even many years after discharge, indicating that surveillance was not the only explanation. Furthermore, an increased risk was noted for cancer of the kidney in women discharged with myxedema (standardized incidence ratios [SIR] = 1.8) and thyrotoxicosis (SIR = 1.3), for cancer of the bladder in women discharged with myxedema (SIR = 1.5) and nontoxic goiter (SIR = 1.3), and for cancer of the hematopoetic system in women discharged with myxedema (SIR = 1.4) and nontoxic goiter (SIR = 1.4). The findings indicate that thyroid disorders may be related to cancer risk of several specific sites other than the thyroid.

[The role of diet for development of renal cell carcinoma]. / Kostens rolle for udvikling af renalcellekarcinoma.

Dietary risk factors for renal cell cancer were investigated in a population based case-control study of incident cases. A total of 351 cases and 340 controls matched for age and sex were interviewed about dietary habits as well as exposure to other known or suspected risk factors. An association was found between risk of renal cell cancer and energy intake, especially fats. There was no protective effect of fruits but a weak protective effect of cruceferous vegetables. The association with diet was present after adjusting for the effect of cigarette smoking, socioeconomic status and body mass index, all of which have been identified as risk factors for renal cell cancer.

[Marital status and survival in colorectal cancer]. / Civilstand og overlevelse ved kolorektal cancer.

We analysed marital status and survival from colorectal cancer among 9596 patients in a nationwide Danish study with complete follow-up of 22-26 years. After exclusion of 2294 patients with missing information, adjusted survival among married patients diagnosed with colon cancer was significantly longer (RR = 0.85; 95% CI: 0.78-0.93). We conclude that marital status does indeed prognosticate long-term survival from colon cancer. These results may have implications for psychosocial intervention after surgery for colorectal cancer.

Influence of marital status on survival from colon and rectal cancer in Denmark.

Survival from colorectal cancer has been analysed in relation to marital status in a nationwide Danish study of 9596 patients with complete follow-up of 22-26 years. After exclusion of 2294 patients with missing information adjusted five-year survival among married patients was significantly longer (RR=0.85; 95% CI 0.78-0.93).

International renal-cell-cancer study. VI. the role of medical and family history.

A number of medical conditions have been linked with renal-cell cancer, although the evidence is not consistent in every case. In a large international case-control study of renal-cell cancer, we examined, among other hypotheses, associations with a personal history of certain medical conditions and a family history of cancer of the kidney or thyroid. Relative risks (RR), adjusted for the effects of age, gender, body-mass index, tobacco smoking and study centre, were significantly increased by a history of kidney stones or thyroid or kidney disease. The RR were not altered by additional adjustment for hypertension, or when diagnoses were restricted to those made at least 5 or 10 years before 1987 (the usual "cut-off" date). The link with kidney injury is particularly likely to be affected by recall bias. Increased RR of borderline significance were found for kidney infection (RR, 1.2) and diabetes (RR, 1.4). Having one first-degree relative with kidney cancer was associated with a significantly increased risk of renal-cell cancer (RR, 1.6; 95% Cl, 1.1-2.4). Seven cases reported 2 first-degree relatives with kidney cancer. No controls had first-degree relatives with kidney cancer. None of our participants reported having von Hippel-Lindau disease. The data suggests that a few conditions of the kidney are strongly associated with renal-cell cancer and that heredity plays a role in a small proportion of cases.

Dietary risk factors for renal cell carcinoma in Denmark.

The role of diet in the aetiology of renal cell carcinoma was investigated in a population-based case-control study in Denmark. Cases were 20-79 years old, with a histologically verified diagnosis of renal cell carcinoma. Controls were sampled from the general population and were frequency-matched on age and sex. A total of 351 cases (73% of the eligible) and 340 controls (68% of the eligible) were included in the study. Dietary information was obtained in a self-administered food frequency questionnaire and the information was confirmed in a subsequent interview performed by trained interviewers who also elicited information on other suspected risk factors such as smoking, occupation, medical history, education and reproductive history. Logistic regression models were used to calculate the odds ratios, and, both frequency of consumption of various food stuffs and computed nutrients were examined. A positive association was observed between risk of renal cell carcinoma and total energy intake (odds ratio, OR, for highest quartile compared to lowest: 1.7 (95% confidence interval, CI, 1.0-3.0) for men, and 3.5 (95% CI 1.6-6.5) for women), fat intake (OR for highest quartile compared to lowest: 1.9 (95% CI 1.1-3.5) for men, and 3.3 (95% CI 1.6-6.9) for women). For women, an effect was also seen for intake of carbohydrates (OR for highest quartile compared to lowest: 3.2 (95% CI 1.5-6.8), while no protective effect was seen for vegetables or fruit. Dairy products may be associated with risk of renal cell cancer (OR for women using thickly spread butter compared to thinly spread: 11.4 (95% CI 2.8-45), OR for women who drank more than one glass of milk with 3.5% fat content compared to never drink milk: 3.7 (95% CI 1.2-11). As expected, total energy intake, intake of fat, protein and carbohydrates were closely correlated making it difficult to identify one of the energy sources as more closely associated with risk of renal cell cancer than the other. Several energy sources have been identified as possible risk factors for renal cell carcinoma. It is possible that a high energy intake as such rather than the individual sources are responsible for the increased risk. Furthermore, dairy fats may be associated with renal cell carcinoma risk. The observed associations appeared stronger in women, and did not explain the association with obesity and low socio-economic status previously found in Denmark.

International renal cell cancer study. VII. Role of diet.

We investigated the role of diet in the etiology of renal cell cancer (RCC) in a multi-center, population-based case-control study conducted in Australia, Denmark, Sweden and the United States, using a shared protocol. A total of 1,185 incident histopathologically confirmed cases (698 men, 487 women) and 1,526 controls (915 men, 611 women) frequency-matched to cases by sex and age were included in the analyses. The association between RCC and diet was estimated by relative risks (RR) and 95% confidence intervals (CI) adjusted for age, sex, study center, body mass index and smoking. A statistically significant positive association was observed for total energy intake (RR = 1.7, 95% CI = 1.4-2.2 for the highest vs. lowest quartile, p value for trend < 0.00001), while the hypothesis that protein and fat are risk factors independent of energy was not supported. Fried meats were associated with increased RCC risk, while vegetables and fruits were protective, with the strongest effect observed for the highest quartile of consumption of orange/dark green vegetables but not vitamin C or beta carotene. Increased risk was associated with low intake (lowest decile) of vitamin E and magnesium. We observed an apparent protective effect of alcohol confined to women and probably due to chance. Our findings indicate an important role of nutrition in the development of RCC. The apparent positive association of energy intake with risk of RCC needs further investigation in a prospective cohort study to exclude the possible impact of differences in recall between cases and controls.

International renal-cell cancer study. VIII. Role of diuretics, other anti-hypertensive medications and hypertension.

Risk of renal-cell cancer in relation to use of diuretics, other anti-hypertensive medications and hypertension was assessed in a multi-center, population-based, case-control study conducted in Australia, Denmark, Germany, Sweden and the United States, using a shared protocol and questionnaire. A total of 1,732 histologically confirmed cases and 2,309 controls, frequency-matched to cases by age and sex, were interviewed. The association between renal-cell cancer and the drugs was estimated by relative risks (RRs) and 95% confidence intervals (CIs). Risks were increased among users of diuretics and other anti-hypertensive medications. After adjustment for hypertension, risk for diuretics was reduced to unity, except among long-term (15+ years) users. Risk for use of non-diuretic anti-hypertensive drugs remained significantly elevated and increased further with duration of use. Overall risk was not enhanced when both classes of medications were used. Excess risk was not restricted to any specific type of diuretic or anti-hypertensive drug and no trend was observed with estimated lifetime consumption of any particular type of product. The RR for hypertension after adjustment for diuretics and other anti-hypertensive medications was 1.4 (95% CI = 1.2-1.7), although among non-users of any anti-hypertensive medications, there was little excess risk associated with a history of hypertension. Exclusion of drug use that first occurred within 5 years of cancer diagnosis or interview did not alter the associations. Our findings suggest small effects on renal-cell cancer risk associated with hypertension and use of diuretics and other anti-hypertensive medications. However, because of potential misclassifications of these highly correlated variables, it is difficult to distinguish the effect of treatment from its indication, hypertension.

International renal-cell cancer study. IV. Occupation.

The relationship between renal-cell cancer (RCC) and occupation was investigated in an international multicenter population-based case-control study. Study centers in Australia, Denmark, Germany, Sweden and the United States interviewed 1732 incident RCC cases and 2309 controls. Significant associations were found with employment in the blast-furnace or the coke-oven industry [relative risk (RR), 1.7; 95% confidence interval (CI), 1.1-2.7], the iron and steel industry (RR, 1.6; 95% CI, 1.2-2.2) and exposure to asbestos (RR, 1.4; 95% CI, 1.1-1.8), cadmium (RR, 2.0; 95% CI, 1.0-3.9), dry-cleaning solvents (RR, 1.4; 95% CI, 1.1-1.7), gasoline (RR, 1.6; 95% CI, 1.2-2.0) and other petroleum products (RR, 1.6; 95% CI, 1.3-2.1). Asbestos, petroleum products and dry-cleaning solvents appear to merit further investigation, in view of the relationship between risk and duration of employment or exposure and after adjustment for confounding. There was a negative association between RCC and education, but it was not consistent across all centers. Overall, the results of our multicenter case-control study suggest that occupation may be more important in the etiology of RCC than indicated by earlier studies.

International renal-cell cancer study. V. Reproductive factors, gynecologic operations and exogenous hormones.

The relationships between reproductive factors, exogenous hormones and renal-cell cancer were examined in an international, multicenter, population-based, case-control study undertaken in 1989-1991. Data from 5 centers situated in Australia, Denmark, Germany, Sweden and the United States included for analysis 608 women with renal-cell cancer and 766 female controls. A significant trend in risk (p = 0.002) was associated with number of births, with an 80% excess risk for 6 or more births [RR = 1.8, 95% confidence interval (CI) = 1.1 to 2.9] compared with one birth. A decreasing risk was seen for increasing age at first birth, although this was confounded by body-mass index and number of births. A suggestive reduction of risk was also seen for increasing age at menarche. Age at menopause was unrelated to risk of renal-cell cancer. An increased risk was observed for women having had both a hysterectomy and an oophorectomy. Use of oral contraceptives in non-smoking women reduced the risk of renal-cell cancer (RR = 0.5, 95% CI = 0.4 to 0.8); this reduction increased with longer duration of use. No association was observed for estrogen replacement therapy. Our results indicate that certain hormonal and reproductive variables may be related to risk of renal-cell cancer and deserve further investigation, both epidemiologically and experimentally.

Cancer incidence in men with Klinefelter syndrome.

Many case reports have suggested an association between Klinefelter syndrome (KS) and cancer, but studies of the cancer incidence in larger groups of men with KS are lacking. A cohort of 696 men with KS was established from the Danish Cytogenetic Register. Information on the cancer incidence in the cohort was obtained from the Danish Cancer Registry and compared with the expected number calculated from the age, period and site specific cancer rates for Danish men. A total of 39 neoplasms were diagnosed (relative risk = 1.1). Four mediastinal tumours were observed (relative risk = 67); all four were malignant germ cell tumours. No cases of breast cancer or testis cancer were observed. One case of prostate cancer occurred within a previously irradiated field. No excess of leukaemia or lymphoma was found. An increased risk of cancer occurred in the age group 15-30 years (relative risk = 2.7). All six tumours in this group were germ cell tumours or sarcomas. The overall cancer incidence is not increased and no routine cancer screening seems to be justified. A considerably elevated risk of mediastinal germ cell tumours occurs in the period from early adolescence until the age of 30.

International renal-cell cancer study. I. Tobacco use.

The relationship between renal-cell cancer (RCC) and tobacco use was investigated in an international, multicenter, population-based case-control study. Coordinated studies were conducted in Australia, Denmark, Germany, Sweden and the United States using a shared protocol and questionnaire. A total of 1,732 cases (1,050 men, 682 women) and 2,309 controls (1,429 men, 880 women) were interviewed for the study. No association was observed between risk and use of cigars, pipes or smokeless tobacco. A statistically significant association was observed for cigarette smoking, with current smokers having a 40% increase in risk [relative risk (RR) = 1.4, 95% confidence interval (CI) 1.2-1.7]. Risk increased with intensity (number of cigarettes) and duration (years smoked). Among current smokers the RR for pack-years rose from 1.1 (95% CI 0.8-1.5) for < 15.9 pack years to 2.0 (95% CI 1.6-2.7) for > 42 pack years (p for trend < 0.001). Long-term quitters (> 15 years) experienced a reduction in risk of about 15-25% relative to current smokers. Those who started smoking late (> 24 years of age) had about two-thirds the risk of those who started young (< or = 12 years of age). Overall, the findings of this pooled analysis confirm that cigarette smoking is a causal factor in the etiology of RCC.

International renal-cell cancer study. II. Analgesics.

There has been concern about the role of analgesics in the development of renal-cell cancer, although a few studies have reported moderately elevated risks with regular or long-term use. In a large international case-control study of renal-cell cancer we examined, among other hypotheses, the effect of phenacetin-containing and of other types of analgesics: paracetamol (acetaminophen), salicylates (mainly aspirin) and pyrazolones (e.g., antipyrine or phenazone). Relative risks, adjusted for the effects of age, sex, body-mass index, tobacco smoking and study centre, were not significantly increased with intake of phenacetin, either when lifetime consumption was categorized at the level of > or = 0.1 kg or when subjects were subdivided further by amount. Nor were paracetamol, salicylates or pyrazolones linked with renal-cell cancer. No consistently increasing risks with consumption level was found. The lack of association was not altered by restricting analgesic use to that which occurred 5 or 10 years before the defined "cut-off" date or when analysis was restricted to exclusive users of a particular type of analgesic. Neither was the risk influenced by the rate of consumption or whether the consumption had occurred at a young age. Our study provides clear evidence that aspirin is unrelated to renal-cell cancer risk, and our findings do not support the hypothesis that analgesics containing phenacetin or paracetamol increase the risk, although the number of "regular" users and the amount of these types of analgesic consumed were too small to confidently rule out a minor carcinogenic effect of phenacetin and paracetamol.

International renal-cell cancer study. III. Role of weight, height, physical activity, and use of amphetamines.

Although numerous studies have identified obesity or high relative weight as a risk factor for renal-cell cancer in women, the degree to which this effect is present in men remains unclear. A multicenter population-based case-control study concerning incident cases of histologically verified renal-cell cancer (n = 1,732) and age- and sex-matched controls (n = 2,309) was conducted in Australia, Denmark, Germany (2 centers), Sweden and the United States. Relative weight was estimated by the body mass index, and the association between this factor and other factors, such as height, physical activity and use of amphetamines, was measured by the relative risk estimated in logistic regression models. Body mass index was found to be a risk factor among women and, to a lesser extent, among men. A 3-fold increased risk (RR = 3.6, 95% CI = 2.3-5.7) was observed for women with a relative weight in the top 5% compared with those in the lowest quartile. Rate of weight change (estimated as weight change per annum in kilograms) appeared to be an independent risk factor among women but not among men. Physical activity and height were unrelated to risk of renal-cell cancer regardless of level of BMI, while use of amphetamines was associated with an increased risk among men, although no dose or duration effect was seen. Our findings verify the link between high relative weight and risk of renal-cell cancer, particularly among women. The mechanism that underlies this association is, however, still unclear, although the rate of weight change may play a role.

[Colorectal cancer in Denmark 1943-1988]. / Kolorektal cancer i Danmark 1943-1988.

Nation-wide incidence rates are presented of colorectal cancer in Denmark from 1943 to 1988. In Denmark notification of malignant and related diseases is mandatory. The percentage of histologically confirmed tumours is now 95. The annual incidence rate of colon cancer in Denmark has been increasing among men and women combined from 684 cases in 1943-1947 to 2020 cases in 1988. In the same period the incidence of rectal cancer has increased from 762 cases in 1943-1947 to 1108 cases in 1988. We analyzed the effects of age, calender time, and birth cohort with multiplicative Poisson models. We did not find consistent period effects in the models. We suggest an etiologic distinction between carcinoma of the rectum, the left colon and the right colon.

Risk of kidney cancer and other second solid malignancies in patients with chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) are known to to have an increased incidence of secondary cancers. We investigated the occurrence of secondary cancers in 7391 patients with CLL diagnosed between 1955 and 1988. The observed number of cancer cases was compared with the expected number of cancers calculated from national cancer incidence rates. The overall risk of cancer was significantly increased among persons with CLL. The standardized incidence ratios (ratio between the observed and the expected numbers) were 2.0 for men and 1.2 for women. Increased risks were found for cancer of the lung and prostate in men (RR = 2.0 and 1.5 respectively), renal parenchyma in both sexes (RR = 2.8 for men, RR = 3.6 for women) non-melanoma skin cancer in both sexes (RR = 4.7 for men, RR = 2.4 for women) and sarcomas (RR = 3.3 for men, RR = 2.8 for women). Although an increased risk of cancer is to be expected solely because individuals with CLL are being physically examined frequently, it appears that the risk is significantly increased for a number of cancer sites in persons with CLL.