Uncovering the aetiology of cancers of unknown primary site

Risk for Cancer of Unknown Primary Site, uncovering the aetiology of a neglected disease – research study

  • Topic: Combination of cancers
  • Institution: Maastricht University
  • Country: Netherlands
  • Status: Ongoing

Co-applicant/s

Prof Piet Van den Brandt, GROW-School for Oncology and Dev Biology, Maastricht University, Netherlands
Dr Caroline Schroten-Loef, Comprehensive Cancer Organization the Netherlands, Netherlands
Dr Rob LH Jansen, Maastricht University Medical Centre, Dept Internal Medicine, Netherlands

Scientific abstract

(View plain language abstract)

Background

Cancer of unknown primary site (CUP) is a metastatic cancer without an identifiable primary origin. In 2010, ~2000 CUP cases were recorded in the Netherlands; the median survival was only three months.

Research regarding the aetiology of this malignancy is extremely limited. Cigarette smoking and waist circumference were associated with CUP risk, and this was heterogeneous with respect to clinical subgroups.

Whether dietary intakes are associated with CUP risk has not been studied yet. We propose therefore to study the aetiology of CUP in a large prospective cohort study with extensive dietary and non-dietary exposure data.

To study possible heterogeneity of associations, CUP will be divided into subgroups defined by sex, histology, pattern of metastasis and survival.

Hypothesis and objectives

In this study, we will investigate whether adhering to recommendations for cancer prevention, as issued by the World Cancer Research Fund (WCRF)/American Institute of Cancer Research (AICR), is associated with a decreased risk of CUP. We therefore propose to study the following hypotheses:

  • The risk of CUP is higher in participants:
    1. who are overweight or obese
    2. who are not physically active
    3. with a low intake of plant foods, i.e. vegetables and fruits
    4. with a high intake of meat and processed meat
    5. with a high intake of alcoholic drinks
    6. who do not adhere to the WCRF/AICR recommendations regarding cancer prevention
  • The risk will differ according to sex, site of metastasis, histology and survival

Settings and methods

The Netherlands Cohort Study on Diet and Cancer (NLCS) is a prospective study and included 120,852 subjects aged 55-69 years at baseline in 1986. Participants completed an extensive questionnaire including a 150-item food frequency questionnaire and questions on smoking habits, body composition and physical activity. Participants were followed for cancer occurrence by record linkage to cancer, pathology and mortality registries. Histologically confirmed cases of CUP (ICD-O-3: C80) will be classified according to site of metastasis using additional information from the cancer registry and from pathology excerpts. For efficiency reasons, a case-cohort method is applied using a subcohort of 5,000 persons randomly sampled immediately after baseline. After 20.3 years of follow-up ~860 histologically verified CUP cases were identified. Exposure to anthropometry, physical activity and dietary factors will be analysed as quintiles or categories (using standard boundaries), and as continuous variables. A sum score will be constructed to measure adherence to the WCRF/AICR lifestyle recommendations. Multivariable Hazard Ratios will be calculated for CUP and for CUP subgroups (defined by sex, histology, pattern of metastasis and prognosis) to levels of the exposures using multivariate Cox regression models, controlling for potential confounders. The minimal detectable HRs for the primary objective with all CUP-cases are moderate (range 0.70-0.72 or 1.38-1.59).

Impact

This study is needed in order to establish whether anthropometry, physical activity, various aspects of diet (intake of plant and animal foods), alcohol consumption, and adherence to WCRF/AICR lifestyle recommendations are associated with risk of CUP, before evidence-based guidelines for prevention can be extended to CUP.

Plain language abstract

Background

Cancer of unknown primary site (CUP) is a metastatic cancer without an identifiable origin. In 2010, ~2000 CUP cases were recorded in the Netherlands; the median survival was only three months.

Research regarding the causes of this cancer is extremely limited. Cigarette smoking and waist circumference were associated with CUP risk, and the strength of the association was different according to clinical subgroups.

Whether dietary intakes are associated with CUP risk has not been studied yet. We propose therefore to study the causes of CUP in a large prospective cohort study with extensive dietary and non-dietary data.

CUP will be divided into subgroups defined by sex, tissue type, pattern of metastasis and survival.

Aims and objectives

In this study, we will investigate whether adhering to recommendations for cancer prevention, as issued by the World Cancer Research Fund (WCRF)/American Institute of Cancer Research (AICR), is associated with a lower risk of CUP. We therefore propose to study the following hypotheses:

  • The risk of CUP is higher in participants: a.who are overweight or obese; b.who are not physically active; c.with a low intake of plant foods, i.e. vegetables and fruits; d.with a high intake of meat and processed meat; e.with a high intake of alcoholic drinks; f.who do not adhere to the WCRF/AICR recommendations regarding cancer prevention.
  • The risk will differ according to sex, tissue type, site of metastasis and survival.

How it will be done

The Netherlands Cohort Study on Diet and Cancer (NLCS) is a prospective study and included 120,852 subjects aged 55-69 years at baseline in 1986. Participants completed an extensive questionnaire on diet and other risk factors for cancer like smoking habits, alcohol consumption, body composition and physical activity. Participants were followed for cancer occurrence by record linkage to cancer, pathology and mortality registries. After 20.3 years of follow-up ~860 histologically verified CUP cases were recorded. Adherence to the WCRF/AICR lifestyle recommendations will be calculated as sum-score. In statistical analyses associations of risk factors (alcohol, vegetables & fruits, meat, weight and physical activity) and adherence to WCRF/AICR recommendations with CUP (including subgroups) will be calculated.

Potential impact

This study will provide evidence whether various aspects of body composition, physical activity, diet (intake of vegetables, fruits and meat), alcohol consumption and adherence to WCRF/AICR lifestyle recommendations are associated with risk of CUP, before evidence-based guidelines for prevention can be extended to CUP.