Clinical trial NCT06450821: PROSpECT-PRIOR-2-CHEMO: PRIOR Dental Intervention Before Chemo to Reduce Chemotherapy Complications
Official title: PROSpECT-PRIOR-2-CHEMO: A Feasibility RCT of Novel Dental Intervention PRIOR[Proactive Intensive Oral Review & Treatment] in Patients Scheduled for Chemotherapy for Myeloma-ASCT & Hematological Cancers to Mitigate Chemotherapy Complications
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Oncology
Periodontitis
Myeloma
Oral Mucositis
Febrile Neutropenia
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: The Leeds Teaching Hospitals NHS Trust
First posted: 2024-06-10
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The moderate and high-risk patients will then be randomised. Those randomised to the PRIOR intervention arm will be assessed in a consultant-led Restorative Dentistry department \& treatment offered to stabilise primary dental diseases (periodontal disease, caries, and odontogenic infection). The treatment plan (by a dentist) will be delivered within the therapeutic window (the PRIOR window), defined as the period between MDT decision to offer ASCT/allo-SCT up to 7 days prior to commencement of CT for ASCT/allo-SCT. Participant treatment plans are highly personalised and therefore number of visits within the therapeutic window to deliver PRIOR are not strictly defined. PRIOR will aim to stabilise the oral health of the participant and remove obvious sources of oral health infection. Participant follow-up will monitor febrile event rate and OM incidence between groups, within the participant therapeutic window, defined as day one of SCT/CT+100 days.
Primary purpose: SUPPORTIVE_CARE

Brief summary: The aim of this feasibility trial is to determine if it is safe and feasible to treat oral health diseases in people with haematological cancers before they start their chemotherapy to reduce complications and disruption to planned chemotherapy dose or schedule.

Detailed description: PROSpECT PRIOR-2-CHEMO is a feasibility trial which will determine if it is safe and feasible to introduce a new oral health (OH) "PRIOR"(Pro-Active Intensive Oral Review and Treatment prior to chemotherapy) intervention for people with cancer, prior to receiving chemotherapy (CT). PRIOR is a novel interdisciplinary intervention that will be introduced into the current oncology pathway and mirrors the specialist Restorative Dental pathway for patients undergoing treatment for Head and Neck cancers. PRIOR is aimed to be delivered within the relatively short therapeutic window that oncology patients have before commencing their scheduled CT for 1) myeloma-ASCT, or 2) Haematological Allograft SCT . This feasibility phase is valuable to inform a definitive trial. The definitive trial would provide important efficacy and mechanistic understanding of the mitigation of CT adverse events (Aes), specifically life-threatening febrile episodes and painful oral mucositis (OM).

The oral microbiome homeostasis is affected by CT; infection risk is exacerbated by OM, and other dental conditions like periodontal disease (PD) that damage the mucosa, caries, and acute / chronic odontogenic abscesses that collectively predispose to systemic translocation of oral-derived bacteria. With about 35% of the adult population affected by moderate and 10-15% severe periodontitis the importance of improving oral health and reducing bacteria load and portals of entry before CT is logical but seldom undertaken.

Bacteria are responsible for the two most prevalent human oral biofilm-mediated diseases: dental caries and periodontitis. Periodontitis is a chronic disease caused by inflammatory reactions to gram negative anaerobic bacteria, resulting in irreversible destruction to oral hard and soft tissues. Local inflammation and tissue damage allow oral bacteria to enter the bloodstream. These Immunocompromised patients (such as those receiving CT) are highly susceptible to these invading pathogens which can manifest as life-threatening systemic infections. The risk of developing systemic infections may be associated with the severity of periodontitis (i.e. the total surface area of the ulcerated pocket epithelium) and the composition periodontal pocket microbiota composition. OM is also an inflammatory condition affecting the oral mucosa. OM is a CT-induced complication that not only affects patient's quality of life but also acts as a portal for oral microorganisms and inflammatory products to translocate into the systemic circulation via the ulcerated mucosa. Pre-existing poor oral and periodontal health is a significant risk factors for CT-induced febrile events, creating therapeutic opportunity.

Oral infection, especially periodontitis, may affect the course and pathogenesis of a number of systemic diseases, including cancer, diabetes, and rheumatoid arthritis. The definitive trial will be a hypothesis-driven, mechanistic trial to understand the novel PRIOR intervention vs current NHS standard of care. Specifically, how PRIOR may mitigate Aes across a range of cancer types and CT regimens. The definitive aim is to understand how PRIOR impacts the oral microbial load, the portal entry sites, and the relationship between the oral microbiome, dysbiosis and systemic infection. The investigators will knowledge transfer from mechanistic evaluation of PD in rheumatoid arthritis showing the oral and gut microbiomes were perturbed but partly normalized after treatment. PD shares common mechanisms of action infection/inflammation across several systemic diseases.

Clinical guidelines recommend seeking dental care prior to CT, this may include recommendation to seek dental care with a general dental practitioner (GDP, Primary care), but uptake is low and established care pathways are rare. Consequently, there has been little direct clinical observation by oncology teams of the value of including dental review; In part due to low advocacy by the oncology team, fuelled by little direct clinical observation of the value of including dental review. Patients report significant barriers to achieving dental care prior to CT including access to a GDP, lack of perceived need and logistical challenges.

Patients do not prioritise seeking dental services as they are unaware of the potential importance to their oncology outcomes. The approach is to provide a specialist consultant-led hospital dental team review mirroring the specialist Restorative Dental pathway undertaken by patients having Head and Neck cancer treatment. Specialist dental teams within a secondary care setting may be better placed to deliver inter-disciplinary care than a GDP due to the time limited therapeutic window (therapeutic window defined as the period between diagnosis and deliver of CT). This work is the first to address the clinical need across several cancer patient groups.

Eligibility criteria: Inclusion Criteria (mod-high/risk trial participants):

* Adults (≥ 18years) with scheduled Chemotherapy. Specifically, patients who meet the following diagnosis and treatment window requirements:

  * Myeloma- Autologous Stem Cell Transplantation (ASCT) before high-dose myeloablative CT.
  * Haematological cancers suitable for Allografts Stem Cell Transplant (SCT) before CT
* Moderate / High Oral Health Risk Assessment - any one of the following:

  * Clinical evidence of caries (2+ teeth)
  * Clinical evidence on soft and hard tissue examination of infection, sinus, swelling or tenderness
  * BPE code 3-4 in any remaining sextant
  * BPE code 1-2 with \>30% BOP
* The patient is fully informed, has received PIS (patient information sheet) and considered during a 'cooling-off' period, is competent to consent, and is able to comply with minimum attendance requirements

Exclusion Criteria:

* Have a history of head and neck radiotherapy
* Have been treated with Denusomab, Bevacizumab, Sunitinib or Aflibercept within 9 months of the MDT date.
* Insufficient teeth \[defined as \<2\]
* Are incapable of providing informed written consent
* Are unable to comply with minimum attendance requirements

Primary outcomes:
measure: Number of participants able to attend treatment sessions required for completion of treatment plan, within the defined chemotherapy therapeutic window.
timeFrame: 100 days from the date of commencement of chemotherapy (about 4 months from randomisation)
Secondary outcomes:
measure: Ability to recruit, recruitment rate and acceptability of randomisation
timeFrame: Prior to commencement of CT and 100 days after CT
measure: Patient compliance with dental referral and treatment plan
timeFrame: Prior to commencement of CT and 100 days after CT
measure: Ability to collect samples (baseline and febrile events) for trial biobank future oral biology testing/mechanistic evaluation
timeFrame: Prior to commencement of CT and 100 days after CT
measure: Data collection via electronic health records
timeFrame: Prior to commencement of CT and 100 days after CT
measure: Number of participants developing sepsis/bloodstream infection/febrile events
timeFrame: 100 days after CT
measure: Number of participants developing oral mucositis and returning the OMDQ questionnaire
timeFrame: 100 days after CT
measure: Number of participants prescribed an Antibiotic
timeFrame: 100 days after CT
measure: Number of participants with hospital admissions and the length of their hospital stays
timeFrame: 100 days after CT
measure: Number of participants with other (specified) chemotherapy-related complications
timeFrame: 100 days after CT
measure: Number of participants completing Quality of Life Questionnaires
timeFrame: 100 days after CT
measure: Rate of Mortality
timeFrame: 100 days after CT
measure: Process Evaluation
timeFrame: post 100 days
measure: Inform the design of a definitive RCT. Specifically, whether haematological cancer groups can be combined for efficiency
timeFrame: After completion of study, approximately 18 months
Other outcomes:
Locations:
city: Leeds
country: United Kingdom
facility: Dental Translational & Clinical Research Unit (DenTCRU)
state: West Yorkshire
Study officials:
affiliation: LTHT
name: Zaid Ali, BChD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Raber-Durlacher JE, Epstein JB, Raber J, van Dissel JT, van Winkelhoff AJ, Guiot HF, van der Velden U. Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer. 2002 Sep;10(6):466-73. doi: 10.1007/s00520-002-0346-3. Epub 2002 Mar 23.
citation: Brennan MT, Elting LS, Spijkervet FK. Systematic reviews of oral complications from cancer therapies, Oral Care Study Group, MASCC/ISOO: methodology and quality of the literature. Support Care Cancer. 2010 Aug;18(8):979-84. doi: 10.1007/s00520-010-0856-3. Epub 2010 Mar 20.
citation: Jia G, Zhi A, Lai PFH, Wang G, Xia Y, Xiong Z, Zhang H, Che N, Ai L. The oral microbiota - a mechanistic role for systemic diseases. Br Dent J. 2018 Mar 23;224(6):447-455. doi: 10.1038/sj.bdj.2018.217.
citation: Zecha JAEM, Raber-Durlacher JE, Laheij AMGA, Westermann AM, Epstein JB, de Lange J, Smeele LE. The impact of the oral cavity in febrile neutropenia and infectious complications in patients treated with myelosuppressive chemotherapy. Support Care Cancer. 2019 Oct;27(10):3667-3679. doi: 10.1007/s00520-019-04925-8. Epub 2019 Jun 20.
citation: Laine PO, Lindqvist JC, Pyrhonen SO, Strand-Pettinen IM, Teerenhovi LM, Meurman JH. Oral infection as a reason for febrile episodes in lymphoma patients receiving cytostatic drugs. Eur J Cancer B Oral Oncol. 1992 Oct;28B(2):103-7. doi: 10.1016/0964-1955(92)90036-z.
citation: Borowski B, Benhamou E, Pico JL, Laplanche A, Margainaud JP, Hayat M. Prevention of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomised controlled trial comparing two protocols of dental care. Eur J Cancer B Oral Oncol. 1994;30B(2):93-7. doi: 10.1016/0964-1955(94)90059-0.
citation: Tsuji K, Shibuya Y, Akashi M, Furudoi S, Yakushijin K, Kawamoto S, Okamura A, Matsuoka H, Komori T. Prospective study of dental intervention for hematopoietic malignancy. J Dent Res. 2015 Feb;94(2):289-96. doi: 10.1177/0022034514561768. Epub 2014 Dec 10.
citation: Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015 Aug;21(8):895-905. doi: 10.1038/nm.3914. Epub 2015 Jul 27.
citation: Momen-Heravi F, Babic A, Tworoger SS, Zhang L, Wu K, Smith-Warner SA, Ogino S, Chan AT, Meyerhardt J, Giovannucci E, Fuchs C, Cho E, Michaud DS, Stampfer MJ, Yu YH, Kim D, Zhang X. Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study. Int J Cancer. 2017 Feb 1;140(3):646-652. doi: 10.1002/ijc.30486. Epub 2016 Nov 23.
citation: D'Aiuto F, Gkranias N, Bhowruth D, Khan T, Orlandi M, Suvan J, Masi S, Tsakos G, Hurel S, Hingorani AD, Donos N, Deanfield JE; TASTE Group. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 2018 Dec;6(12):954-965. doi: 10.1016/S2213-8587(18)30038-X. Epub 2018 Oct 24.
citation: Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K, Rosen A, Nigrovic PA, Sokolove J, Giles JT, Moutsopoulos NM, Andrade F. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci Transl Med. 2016 Dec 14;8(369):369ra176. doi: 10.1126/scitranslmed.aaj1921.
citation: Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007 Mar 1;109(5):820-31. doi: 10.1002/cncr.22484.