The oral cavity as a source of febrile neutropenia, an observational study in cancer patients treated with myelosuppressive chemotherapy

Febrile neutropenia (FN) is a clinically important adverse effect of
myelosuppressive chemotherapy. If patients present with FN, attention is
focused on well-recognized sites of origin of infection: the airways, urinary
tracts, and skin. However, infections can be only documented clinically in
about two-third of febrile episodes, whereas a causative microbial pathogen
cannot be identified in the majority (>70%) of cases.
Pre-treatment oral evaluation aimed to identify and eliminate oral/dental foci
is only routinely used in patients at high risk for oral complications (i.e.
head and neck cancer patients and stem cell transplantation recipients).
However, any patient treated with myelosuppressive chemotherapy, be it for cure
or palliation, is at risk of developing infection in and/or originating from
the oral cavity. Nevertheless, in these patients dental screening is somewhat
randomly employed at the oncologist*s discretion.
More insight into the pre-treatment oral condition and its potential role in FN
is mandatory, particularly considering the growing numbers of older patients
retaining their natural dentition and the increase of dental diseases and
cancer incidence with age.
In addition, oral diseases may aggravate chemotherapy-induced oral mucositis
(OM). OM is associated with an inflammatory response, which together with
ulcerations providing a portal of entry for bacteria, can result in FN and
systemic inflammatory syndrome (SIRS) and/or sepsis. Evidence suggests that
microorganisms are involved in the pathobiology of OM, but no longitudinal
studies using open-end sequencing are available.
Furthermore, comparing bacteria identified in blood cultures in febrile
patients with those of the oral cavity will expand our knowledge on the role of
the oral cavity as a potential source of bacteremia.
We expect that our results will provide a scientific base for subsequent
intervention studies on the efficacy of dental screening and elimination of
foci, and other interventions aimed at modifying the oral environment before
and during chemotherapy.

Overall aim
The overall aim is to assess whether associations can be identified between the
presence of oral/dental foci, the composition of the oral microbiome, the
incidence and severity of OM, and the risk to develop FN in cancer patients
treated with myelosuppressive chemotherapy.

Primary objective:
- To identify oral/dental foci prior to the start of chemotherapy and to
determine whether these are associated with the development of FN, bacteremia
and/or SIRS/sepsis

Secondary objectives:
- To assess whether oral/dental foci are associated with the incidence and
severity of OM
- To assess whether OM is associated with FN, bacteremia and SIRS/sepsis
- To document microbiological shifts (bacteria/fungi) in oral rinsing samples
taken prior to chemotherapy and during standard care visits thereafter using an
open-end technique and to investigate potential associations with the
development of OM
- To assess retrospectively whether any microorganisms found in blood samples
from patients with FN are (likely) derived from the oral cavity using DNA
finger printing techniques and Q-PCR.
- To explore whether genetic polymorphisms in candidate genes demonstrate an
increased risk for the development of severe OM, FN, and SIRS/sepsis
- Differences in inflammation parameters in peripheral blood at baseline and
when presenting with fever and/or mucositis.

A single-center prospective observational study.

The burden for patients is minimal, as the study is observational. It involves
a non-invasive pre-chemotherapy oral examination, and collecting of oral
rinsing samples (during standard care visits). In patients presenting with FN,
blood samples are taken routinely as part of standard care. There are no risks
or benefits for participating subjects. The anticipated knowledge gained from
this study will help to improve future supportive care protocols.