Module 3 - Strategic case studies in practice

Palli, Russo, and Decarli (2001) Pobel et al. (1995) Pottegård, A et al. (2018) Song, Wu, and Guan (2015) Zheng et al. (2018)

Dietary and familial determinants of 10-year survival among patients with gastric carcinoma Nitrosamine, nitrate and nitrite in relation to gastric cancer: A case- control study in Marseille, France Use of N- nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study Dietary nitrates, nitrites, and nitrosamines intake and the risk of gastric cancer: A meta-analysis Dietary N- nitroso compounds and risk of pancreatic cancer: Results from a large case-control study Dietary N- nitroso compounds and risk of colorectal cancer: A case-control study in Newfoundland and Labrador and Ontario, Canada

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Zhu et al. (2014)

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2.4.6.1. Epidemiological studies on the association of potent mutagenic N-nitrosamines in medicinal products with the risk of cancer Currently, only one epidemiological study on the effect of N- nitrosamines in medicinal products on the risk of cancer has been published ` This study, based on Danish nationwide health registries, did not detect an increase in overall cancer risk or in any of the examined cancer types in patients that have been exposed to NDMA contaminated Valsartan. However, the study sample size is limited to 5,150 patients with overall 302 cases of cancer, and the average follow-up time is limited to 4.6 years. The limited sample size prevented the study from detecting possible smaller effects. To detect small short- term effects, a larger study population is necessary. Furthermore, longer follow-up times are needed to assess an excess lifetime risk. CHMP was also informed about unpublished preliminary data from a cohort study on 780,000 patients using valsartan with over 400,000 potentially exposed to NDMA by contaminated valsartan batches. The preliminary results suggest an increase in liver cancer diagnosis of 16% in potentially NDMA exposed patients, however a meaningful evaluation was not possible due to the limited information available. 2.4.6.2. Epidemiological studies on the association of potent mutagenic N-nitrosamines from dietary sources with the risk of cancer The effect of N- nitrosamines on the risk of cancer has been the subject of epidemiological research in the last few decades. The association of N- nitrosamines on subsequent carcinogenesis has been studied mostly via monitoring of dietary intake with few exceptions studying for example exposure by rubber dust (e.g. Hidajat et al. (2019)). In the following, studies on the association of N- nitrosamines and cancer risk in the context of dietary N- nitrosamine intake are summarised. The associations of the risk of several cancer types with dietary intake of N- nitrosamines have been the subject of epidemiological studies. By recording dietary habits with questionnaires and classifying all nutritional components, the studies aimed to investigate associations of N- nitrosamines with the risk of cancer. Dietary habits were either recorded prospectively or, in the case of case control designs, retrospectively. In the latter design, cases refer to patients with incident cancer and controls are collected from the base population. Regarding the influence of N- nitrosamines, these studies mostly focussed on the association of cancer risk after the dietary intake of NDMA.

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