Incidence and Severity of Oral Mucositis after High- Dose Melphalan in Stem Cell Transplant Patients: A Pilot Study of Oral Cryotherapy

Research Article

Ann Hematol Oncol. 2016; 3(4): 1085.

Incidence and Severity of Oral Mucositis after High- Dose Melphalan in Stem Cell Transplant Patients: A Pilot Study of Oral Cryotherapy

Kanz BA¹, Savani BN² and Culos KA1,2*

¹Department of Pharmaceutical Services, Vanderbilt University Hospital, USA

²Department of Hematology/Oncology, Vanderbilt Ingram Cancer Center, USA

*Corresponding author: Culos KA, Department of Pharmaceutical Services and Department of Hematology/ Oncology, Vanderbilt University Hospital, Room 2639 The Vanderbilt Clinic, 1301 Medical Center Drive, Nashville, TN 37232, USA

Received: May 07, 2016; Accepted: June 20, 2016; Published: June 22, 2016


Background: Oral mucositis (OM) results in morbidity for patients undergoing stem cell transplant (SCT) with a melphalan-based conditioning regimen. Oral Cryotherapy (OC) may prevent damage to the mucosa. Starting September 1, 2014, a 75-minute, standardized, OC protocol was implemented at Vanderbilt Ingram Cancer Center (VICC). This study evaluated the incidence and severity of OM before and after the institution of the protocol. A unique feature of this report is that the majority of patients underwent SCT in the outpatient setting.

Methods: This was a matched cohort retrospective chart review of adult patients who received an autologous SCT after a conditioning regimen containing high-dose melphalan (140-200 mg/m2) between September 1, 2013 and January 31, 2015. The primary outcomes were the incidence and severity of OM, measured using the National Cancer Institute Common Toxicity Criteria (NCI-CTC), from the administration of melphalan through engraftment. Secondary outcomes included hospitalizations, use of parenteral nutrition or patient controlled analgesia, and incidence of febrile neutropenia.

Results: Forty-one patients were in each cohort. The incidence of clinically relevant OM (=NCI-CTC grade 2) was lower in patients who received OC [10/41 (24%) vs. 29/41 (71%), p-value <0.05]. Patients who received OC but still developed OM were more likely to have grade 1 mucositis versus grade 2 or above as in the control cohort. There were no significant differences in secondary outcomes.

Conclusion: OC reduces OM in patients undergoing autologous SCT with melphalan conditioning. A75-minute OC protocol is effective and feasible for use in patients transplanted in multiple settings.

Keywords: Mucositis; Cryotherapy; Melphalan; Stem cell transplant; Regimen related toxicity


ASCT: Autologous Stem Cell Transplant; ADL: Activities of Daily Living; EMR: Electronic Medical Record; FDA: Food and Drug Administration; GM-CSF: Granulocyte Macrophage Colony- Stimulating Factor; HD-Mel: High-dose Melphalan; NCI-CTC: National Cancer Institute Common Toxicity Criteria; OC: Oral Cryotherapy; OM: Oral Mucositis; SCT: Stem Cell Transplant; VICC: Vanderbilt Ingram Cancer Center


High dose melphalan (HD-Mel, 140-200 mg/m²) is the standard of care conditioning regimen in patients with multiple myeloma preparing for autologous stem cell transplant (ASCT) [1]. While it is effective, it is associated with significant toxicity. With HD-Mel conditioning regimens, up to 80% of ASCT patients will experience oral mucositis (OM), ranging in severity from grade 1 through grade 5 per the National Cancer Institute Common Toxicity Criteria OM Scale (NCI-CTC) [2,3].

Clinical consequences of OM include dehydration, malnutrition, infection and reduced long-term survival [2]. Secondary consequences include increased use of parenteral narcotics and increased days requiring total parenteral nutrition. The typical time course of OM involves it’s development five to seven days after chemotherapy exposure with symptoms persisting until after engraftment (approximately day fourteen after transplant) [2].

A Cochrane Review from 2011 identified ten methods explored to prevent or reduce the severity of OM, and concluded only palifermin and oral cryotherapy (OC) had evidence to prevent mucositis [4]. Palifermin, a keratinocyte growth factor, is the only Food and Drug Administration (FDA) approved therapy for prevention of OM in SCT patients. Opponents of this therapy cite limitations of the approval studies for small sample sizes and lack of comparisons to other available mucositis prevention strategies [5,6].

OC is the practice of decreasing the temperature of the oral mucosa by swishing ice water or chewing ice chips prior to, during, and after chemotherapy administration. It is postulated to reduce OM by constricting blood vessels in the mucosa, decreasing exposure of the mouth to the offending agent [2,7]. A second proposed mechanism of action is that cryotherapy reduces the metabolic function of epithelial and basal cells providing a cytoprotective effect [7]. Multiple studies have shown OC to be an effective treatment to prevent OM in patients treated with HD-Mel [7-10]. While there are no head-to-head studies comparing OC to palifermin, OC does provide a financial benefit with limited safety implications and is recommended as a preventative therapy by both the National Comprehensive Cancer Network (NCCN) and the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ ISOO) in their respective guidelines [11,12].

Starting September 1, 2014, a standardized cryotherapy protocol was implemented in all ASCT patients receiving HD-Mel at Vanderbilt Ingram Cancer Center (VICC) (Figure 1). Patients at VICC are transplanted as outpatients, unless they have variables indicating a high-risk transplant warranting inpatient monitoring. Patients receive cryotherapy education and are instructed to chew ice for a total of seventy-five minutes, including thirty minutes prior to their infusion, during the fifteen-minute infusion, and thirty minutes after the infusion. This single center, retrospective, matched cohort study was conducted to evaluate the incidence and severity of OM before and after the institution of a standardized OC protocol.