Judith Zecha

Cancer is the leading cause of death globally, with 19.3 million new cases and 10 million deaths recorded in 2020. In Europe, including the Netherlands, it’s the primary cause of premature mortality. Patients diagnosed with a solid tumor or lymphoma often receive myelosuppressive chemotherapy (CT) a (part) of their treatment regimen. Myelosuppressive CT houses different risks and potential complications; of which one of them is febrile neutropenia.

Febrile neutropenia (FN) is a critical condition defined by fever during a period of neutropenia. FN is seen as a medical emergency as fever may be the first and only sign of infection in neutropenic patients, and can potentially lead to life-threatening conditions. Despite extensive diagnostic evaluations, including detailed patient histories, physical examinations, radiographic imaging, and microbiological tests, a causative microbial pathogen is identified in less than 30% of these cases, highlighting the diagnostic challenges associated with FN. This outlines an overview of the research conducted in this PhD thesis, focusing on the potential contribution of the oral cavity in the development of FN.

Chapter 2
The contribution of the oral cavity in the development of FN is not fully understood. Chapter 2 reviews the potential role of the oral cavity in relation to FN in patients treated with myelosuppressive CT. It discusses CT-induced adverse oral side effects such as mucositis and oral infections and the impact of CT regimens on the oral ecosystem, as CT may contribute to oral dysbiosis. A potential relationship between OM and FN is reported, but not fully elucidated. In addition, poor oral hygiene and pre-existing oral infections might aggravate the severity and duration of OM and therefore contribute to the development of FN. Other mucosal infections, like viral or bacterial infections, may also have a contribution in developing FN. However, these infections are clinically difficult to differentiate from OM. Furthermore, evidence suggest that dental pathologies (“dental foci”), particularly periodontitis, might also contribute to developing FN. Knowledge about the potential role of other dental infections is scarce. The current evidence is mainly based on small and retrospective studies involving patients treated with high-dose CT with or without hematopoietic cell transplantation. In conclusion, dental evaluation and work up of high-risk patients should be integrated in the patient’s work up before tumor treatment. However, further research is needed to give more insight in the potential role of the oral cavity in the development of FN and infectious complications. Especially, in patients treated with CT for solid tumor or lymphoma, as the current evidence is scarce for this patient group.

Chapter 3 is devoted to OM, which can be induced by cytotoxic cancer therapies. Oral mucositis, which is an inflammatory condition, poses a significant clinical challenge, as it is characterized by severe pain and may necessitate interruptions or dose reductions in treatment regimens. Oral mucositis negatively affects the patient’s quality of life and may lead to decreased survival, particularly in immunocompromised individuals. The incidence of OM induced by different treatment regimens, the pathobiology, risk factors for developing OM, clinical presentation and management of OM are discussed. Furthermore, it discusses advancements in targeted anticancer therapies and oral mucosal side effects and proposes future research directions.

Chapter 4 presents the results of the longitudinal prospective observational study, conducted in patients diagnosed with solid tumors and lymphoma undergoing myelosuppressive chemotherapy. The research question investigated was the potential role of the oral cavity in developing FN. Participants underwent a dental examination before the start of CT-regimen and all oral infections were noted. During and after the CT-regimen, the presence and severity of OM was scored, as well as signs and symptoms of oral/dental infections. When a patient presented with fever, a full body examination, including laboratory/microbiological/imaging investigation was performed. Furthermore, the oral cavity was inspected and the presence and severity of OM was scored.

The study revealed that 44.3% of the patients were diagnosed with a dental focus before the start of CT-regimen. During CT-regimen 53.4% developed oral mucositis, of which patients developed ulcerative mucositis (WHO grade 2 or higher). Of the included patients, 11.4% developed FN during the follow-up period. A significant relation between ulcerative OM and the development of FN was found. Furthermore, mucositis risk was associated with the myelotoxicity of CT. However, no significant relation could be established between the presence of dental foci prior to chemotherapy and the development of FN.

Chapter 5
Pre-chemotherapy oral examination to identify foci of infection is recommended, but it is unclear whether this should include panoramic radiography. In chapter 5, a study is conducted to evaluate the additional diagnostic merit of panoramic radiography as part of pre-CT oral screening. Patients with solid tumors scheduled to receive myelosuppressive CT were eligible for inclusion. Foci definition followed the guidelines of the Dutch Association of Maxillofacial Surgery. Oral foci assessed by clinical evaluation and by panoramic radiography were compared. In 33 out of 93 patients (35.5%), one or more foci could be identified by clinical examination, whereas in 49.5% of patient’s panoramic radiography showed pathology. In 19 patients, an oral focus had been missed by clinical examination only, whereas in 11 patients panoramic radiography indicated periodontal bone loss, but advanced periodontitis was not substantiated by clinical examination. In conclusion, panoramic radiographs complement clinical examination and have additional diagnostic value. Nevertheless, the additional merit seems small and the clinical relevance may vary depending on the anticipated risk of developing oral complications and the need of detailed diagnosis and rigorous elimination of oral foci prior to the start of cancer therapy.

Chapter 6
In chapter 6, the possible changes of the oral microbiota during myelosuppressive CT were evaluated and the potential relationship between the oral microbiome, the presence of OM and FN was evaluated. To this end, rinsing samples of participants in our observational study were retrieved before, during and after the start of CT, but also when OM or FN was present. The samples were analyzed using 16S rRNA gene amplicon sequencing and alpha (Shannon) and beta (PERMANOVA) diversity was calculated. Furthermore, differential abundances were analyzed using ALDEx2v1.32.0. Differences between groups were calculated using the Mann Whitney U-test, Kruskal-Wallis test and Wilcoxon Signed Rank using R. The results showed significant changes in alpha diversity when OM was present. Moreover, significant changes were seen in beta diversity during the course of the CT treatment and when OM was present. Genera showing substantial changes in relative abundance were Streptococcus during the course of CT treatment and Prevotella, Fusobacterium, Selenomonas, Actinomyces and Leptotrichia in the presence of OM. In conclusion, changes in the oral microbiota were seen during the CT-regimen and when OM was present. Furthermore, a potential change of the oral microbiota occurred during FN episodes; however, larger studies should be performed to substantiate our results.