Anders Mellemgaard

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer

PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 (n = 863) or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P <or= .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Obesity and cancer risk : a danish record-linkage study

A cohort of 43,965 obese persons was accrued on the basis of discharge registrations from Danish hospitals, and incidence of cancer in the cohort was compared to that in the Danish population as a whole using indirect standardisation for age and period. Increased incidence was observed for cancer of the uterine corpus independently of age [114 cases, relative risk (RR) = 2.0, confidence interval 1.6-2.4], and for breast cancer in women above the age of 70 (133 cases, RR = 1.2). These findings are consistent with previous studies. In younger women, breast cancer occurred less frequently and ovarian cancer occurred more frequently than expected. Increased incidence was observed for cancers of the oesophagus (26 cases, RR = 1.9) and the liver (58 cases, RR = 1.9), probably reflecting an increased prevalence of excessive alcohol consumption in the cohort. Increased incidence was furthermore observed for cancers of the pancreas (101 cases, RR = 1.7), the prostate (96 cases, RR = 1.3) and the colon (195 cases, RR = 1.2), which may indicate the existence of risk factors which are common to obesity and to these cancers, for example, dietary habits. Kidney cancer was increased in women only. Overall, the incidence of cancer was increased by 16% in the cohort. The results were essentially unchanged by restriction to the subcohort of 8207 persons in whom obesity was the primary discharge diagnosis, and were also similar in the first year of follow-up after hospital discharge. Selection bias is, therefore, not likely to have influenced the results.

Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial

BACKGROUND The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). METHODS Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m(2) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. FINDINGS Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8-11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9-3·9] vs 2·7 months [2·6-2·8]; hazard ratio [HR] 0·79 [95% CI 0·68-0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8-36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5-12·6] vs 7·9 months [6·7-9·1]; HR 0·75 [95% CI 0·60-0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6-15·1] vs 10·3 months [95% CI 8·6-12·2]; HR 0·83 [95% CI 0·70-0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8-11·2] vs 9·1 months [8·4-10·4]; HR 0·94, 95% CI 0·83-1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). INTERPRETATION Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. FUNDING Boehringer Ingelheim.

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 β 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. 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.

Risk factors for renal cell carcinoma in Denmark. I. Role of socioeconomic status, tobacco use, beverages, and family history.

Risk factors for renal cell carcinoma were examined in a population based case-control study in Denmark. A total of 368 cases and 396 age- and gender-matched controls were interviewed in their homes. Increased risk was associated with low socioeconomic status. For men, an increasing risk with decreasing socioeconomic status was seen (odds ratio [OR]=2.2, 95 percent confidence interval [CI]=1.0–4.6 for men in the lowest socioeconomic stratumcf the highest). For women, the risk was lower in the highest socioeconomic stratum compared with the rest (OR=2.4, CI=0.9–5.9 for the lowest stratacf the highest). Cigarette smoking was a risk factor in men with an OR=2.3 (CI=1.1–5.1) for cigarette smokers with a total consumption of more than 40 pack-years compared with nonsmokers. Family history of kidney cancer was associated with an increased risk in both genders (for men, OR=4.1, CI=1.1–14.9; for women, OR=4.8, CI=1.0–23). Observations were inconsistent regarding coffee and alcohol consumption, and we found no association with tea drinking. The association with socioeconomic status remained after adjustment for other factors.

Incidence of second primary cancer following testicular cancer

The incidence of second primary cancers was investigated in 6187 Danish men diagnosed with testicular cancer in the period 1943-1987. During the course of 59,000 person years, 459 subsequent primary cancers occurred. The relative risks were significantly increased for leukaemia, gastric cancer, pancreatic cancer, bladder cancer, non-melanoma skin cancer and kidney cancer. Increased incidence was furthermore suggested for cancer of the rectum, prostate and lung. The increased incidence of leukaemia appeared in the first 10 years after testicular cancer diagnosis. The excess incidence for gastric cancer, pancreatic cancer, rectal cancer and lung cancer was strongest 10-19 years after testicular cancer, while the relative risk of non-melanoma skin cancer and prostate cancer increased throughout the period of follow-up. The increased incidence of cancer in this cohort is most likely an effect of radiotherapy used for testicular cancer. It is proposed that the different incidence patterns over time after testicular cancer diagnosis reflect differences in the growth rate of tumours originating in different tissues.

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.

Different Impact of Excision Repair Cross-Complementation Group 1 on Survival in Male and Female Patients With Inoperable Non–Small-Cell Lung Cancer Treated With Carboplatin and Gemcitabine

PURPOSE The excision repair cross-complementation group 1 (ERCC1) status was assessed in patients receiving carboplatin and gemcitabine for inoperable non-small-cell lung cancer (NSCLC). We analyzed the association between the ERCC1 status and the overall survival after the chemotherapy. PATIENTS AND METHODS We retrospectively identified 163 patients with inoperable NSCLC and sufficient tumor tissue for ERCC1 analysis, who had received carboplatin and gemcitabine as first-line treatment. Immunohistochemistry was used to assess the expression of ERCC1. RESULTS One hundred sixty-three patients were included. Seventy (42%) were ERCC1 positive. Patients treated with carboplatin and gemcitabine and having ERCC1-negative tumors had a significantly increased survival when compared to patients with ERCC1-positive tumors (median survival, 12.0 months v 8.2 months; P = .02). This difference was mainly seen in men, where those with ERCC1-negative tumors had a significantly increased survival compared to men with ERCC1-positive tumors (median survival, 11.8 months v 7.9 months; P = .005). Conversely, women who were ERCC1 negative did not have a survival advantage over ERCC1-positive women. CONCLUSION We confirmed previous reports that ERCC1 expression is predictive for outcome in patients treated with carboplatin and gemcitabine. Patients with ERCC1-negative tumors had an increased survival compared to patients with ERCC1-positive tumors and this difference was mainly attributable to a survival difference among men.

ERCC1 and Ki67 in Small Cell Lung Carcinoma and Other Neuroendocrine Tumors of the Lung: Distribution and Impact on Survival

Background: Excision repair cross-complementation group 1 (ERCC1) is a key component of the platinum-DNA repair mechanism. Ki67 is associated with the clinical course of several malignancies. The associations of ERCC1 and Ki67, clinical features and survival in small cell lung carcinoma (SCLC), typical carcinoid (TC), atypical carcinoid (AC), and large cell neuroendocrine carcinoma (LCNEC) were determined. Materials and Methods: We included a consecutive series of 186 patients with SCLC treated with platinum-based chemotherapy and surgically treated patients with TC (n = 48), AC (n = 15) and LCNEC (n = 27). ERCC1 and Ki 67 were measured by immunohistochemistry and scored using published criteria. Results: The expression of ERCC1 was different among the different tumor types (p < 0.001). For patient with limited disease as well as extensive disease SCLC, no association of ERCC1 expression with survival was observed (p = 0.59). However, only 10% of SCLC tumors expressed ERCC1. For TC and AC, ERCC1 positive patients had better survival than ERCC1 negative patients. ERCC1 had no prognostic impact for LCNEC. A difference of the percentage of Ki67 LI was observed for the different tumor types (p < 0.001). The difference between TC and AC was significant (p = 0.02), as was the difference between low grade (TC+AC) and high grade NE (LCNEC + SCLC) (p < 0.001). For all included patients, a correlation between Ki67 and ERCC1 was observed (RSquare = 0.19, p < 0.001). Conclusion: ERCC1 expression in SCLC treated with platinum-based chemotherapy has no impact on survival. High expression of ERCC1 in TC might represent a clue to the failure of platinum-based therapy in these patients. ERCC1 expression has prognostic impact in lung carcinoids. Ki 67 might be considered as a supplementary test to the histopatologic classification of NE tumors.