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Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study

Bone Marrow Transplantation volume 52, pages 154–156 (2017)Cite this article

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Oral mucositis (OM) occurs in 50–80% of patients treated with high-dose chemotherapy as conditioning for hematopoietic stem cell transplants,1 and causes significant morbidity and economic impact.2 The current guidelines of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO)3 only suggest the use of cryotherapy to prevent OM in patients who received high-dose melphalan (HDM) and autologous stem cell transplant (ASCT), but a strong recommendation is not possible, considering the limited number of prospective, well-designed randomized studies. However, there are several reports supporting the efficacy of cryotherapy in preventing OM in this setting of patients. From a critical review of these retrospective4, 5, 6, 7, 8, 9 and prospective1, 10, 11, 12 studies, it seems that oral cryotherapy by applying ice chips or ice cold water during high-dose chemotherapy or 15–30 min before and continued until 6 h after the end is able to significantly decrease the incidence of grade 3–4 OM (from 23–85% to 3–33%). However, only few data have been obtained from prospective randomized trials11, 12 and many studies included patients treated with anthracyclines-based chemotherapy before ASCT, and for this reason at major risk of OM.13 Moreover, consistent data regarding the impact of cryotherapy on infectious episodes after ASCT are lacking.

From October 2013 to January 2016, 72 consecutive patients with multiple myeloma who underwent ASCT after HDM (200 mg/m2) were enrolled in this study. Patients were randomly assigned to receive (arm A, n=36) or not (arm B, n=36) OM prophylaxis, consisting of local cryotherapy during the chemotherapy administration. Patients were allocated to each arm on the basis of a standard randomization process carried out by the biostatistics unit. All patients signed a written informed consent and the study was approved by the Ethical Committee of our institute, in compliance with the Helsinki declaration (Prot. RS-760). Eligibility criteria included patients aged ⩾18 years, who underwent a first ASCT after induction treatment with thalidomide, bortezomib and dexamethasone (VTD). Patients who had experienced previous episodes of OM or with previous exposure to anthracyclines or neck/head radiotherapy were excluded. The primary end point was to determine whether the use of oral cryotherapy could be useful to reduce the occurrence of grade 3–4 OM compared with the control group. Secondary end points were to compare: (1) occurrence of all OM grades; (2) need of total parenteral nutrition (TPN) and opioids; (3) occurrence of fever of unknown origin (FUO) during neutropenia and microbiologically documented infections; and (4) overall need of IV antibiotics between the two groups. FUO was defined as a temperature >38.3 °C occurred during neutropenia or after neutrophil recovery, with no obvious infectious source despite appropriate investigation. Melphalan administration consisted of two doses each of 100 mg/m2 administered in a 1-h long infusions both given at day −2 and separated by 2 h. On day −2, patients assigned to arm A received ice chips with rounded corners in their mouth during chemotherapy infusion. When the ice melted, it was immediately replaced; the entire procedure was monitored by a nurse. OM was assessed daily using the National Cancer Institute Common Toxicity Criteria version 4.02. Patient pain due to OM was monitored daily using the numerical rating scale. In case of sever and uncontrolled pain, IV opioids were administered. Moreover, in case of significant weight loss (>5% of basal) due to limited food intake, a TPN was started. All patients underwent an uniform anti-infectious and support therapy. In particular, 500 mg of ciprofloxacin was administered twice daily from day 0 until neutrophilis recovery (>500/μL for three consecutive days). Cotrimoxazole 800/160 mg twice weekly and valaciclovir 1 g daily were administered from day −2 and continued for at least 6 months after transplant. Hydro-electrolytic and transfusion support was in accordance with standard operating procedures. Febrile neutropenia prophylaxis with filgrastim 5 μg/kg was administered in all patients at day +3 after transplant until neutrophilis recovery. All patients underwent mouth rinses with oral nystatin-based protocols three times daily. Patients were hospitalized and remained inpatients for all the duration of the study.

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Acknowledgements

We thank Cecilia Fagioli and Federica Falcioni for their technical study support. We thank Tania Merlino (English mother tongue) for reviewing the use of the English language.

Author contributions

Concept and design: MF; development of methodology: MF and MA; acquisition of data: VC, GS, RD, FL, CG, RM, PF, PF, RA, SA, PA and CM; data analysis and interpretation: MF, MA and GD; technical and statistical support: GD, PE and CM; manuscript writing: MF; and critical review of the manuscript: TA, AW and MA.

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Authors and Affiliations

  1. Hematology and Stem Cell Transplant Unit, Regina Elena National Cancer Institute, Rome, Italy

    F Marchesi, C Viggiani, S Gumenyuk, D Renzi, G Caffarella, F Palombi, F Pisani, A Romano, A Spadea, E Papa, A Pignatelli & A Mengarelli

  2. Hematology, S Eugenio Hospital, Rome, Italy

    A Tendas

  3. Biostatistics Unit, Regina Elena National Cancer Institute, Rome, Italy

    D Giannarelli & M Canfora

  4. Hematology Unit, Tor Vergata University, Rome, Italy

    L Franceschini, M Rizzo, M Cantonetti & W Arcese

  5. Rome Transplant Network, Rome, Italy

    W Arcese

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  1. F Marchesi
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Correspondence to F Marchesi.

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Marchesi, F., Tendas, A., Giannarelli, D. et al. Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study. Bone Marrow Transplant 52, 154–156 (2017). https://doi.org/10.1038/bmt.2016.207

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