A Cold, Hard Solution for Oral Mucositis

Kristin Jenkins

September 13, 2016

Oral cryotherapy, which is the cooling of the mouth with cold consumables, is effective for the prevention of oral mucositis in the setting of fluorouracil (FU)-based chemotherapy for solid cancers, say experts in a Clinical Evidence Synopsis published online September 1 in JAMA Oncology.

It also prevents severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT), according to the synopsis, which is based on a 2015 Cochrane review.

"Oral cryotherapy offers a simple, noninvasive, non-toxic, and cost-effective prophylactic option for preventing oral mucositis," write the synopsis authors, led by Martin G. McCabe, PhD, from the Institute of Cancer Sciences at the University of Manchester, United Kingdom, and colleagues.

Should clinicians be advising their patients with cancer to pack a cooler of ice chips before heading to chemo?

"We don't know!" Dr McCabe told Medscape Medical News. "Oral cryotherapy is a bit of a mixed bag, and we don't yet know if there is a difference between, say, sucking ice cubes versus crushed ice versus flavored ice lollies."

"We also don't know the optimal timing, frequency or mode of delivery of the intervention, including whether it should be every day, several times a day, before, during or after treatment, and for how long it should be continued."

Most patients tend to experiment on their own with ice chips, said Anurag K. Singh, MD, professor of medicine at the University at Buffalo School of Medicine, New York, in an interview with Medscape Medical News. "Most do not continue the practice," he added.

Dr Singh, who was not involved in the synopsis, also noted that physicians should not be recommending oral cryotherapy for all chemotherapy patients because "the data are really just for 5-FU and melphalan BMT [bone marrow transplantation]."

Oral mucositis affects up to 75% of patients receiving chemotherapy, radiotherapy of the head and neck, or targeted therapy. The synopsis authors estimate that the associated costs, including increased use of opioid analgesics, hospitalization, nasogastric or intravenous nutrition, and possible disruption of cancer therapy, can add up to more than $42,000 per patient.

For the synopsis, the researchers looked at 14 randomized controlled trials conducted in the United States, Iran, Italy, Turkey, Canada, Denmark, Sweden, and China from the late 1980s to 2013 and published between 1990 and June 17, 2015.

A total of 1316 patients were randomly assigned to cryotherapy vs no treatment or standard oral care, one cryotherapy regimen vs another, cryotherapy vs chlorhexidine, and cryotherapy vs leucovorin rinses. In all, 1280 patients were analyzed, 60% of whom were male and 40% female. Median age ranged from 36 to 63 years.

In an interview, Nathaniel S. Treister, DMD, DMSc, from the Division of Oral Medicine and Dentistry at Brigham and Women's Hospital, Boston, Massachusetts, said that oral cryotherapy "appears to be used widely throughout US cancer centers for prophylaxis of oral mucositis. It is an effective, safe, and low-cost prophylactic intervention that can potentially reduce the severity of oral mucositis in select cancer patients undergoing chemotherapy."

Dr Treister is the author of an online report on chemotherapy-induced oral mucositis. Others agree. "Swishing ice chips in the mouth for 30 minutes around the time of chemotherapy…'may provide a very inexpensive and effective way to prevent or minimize mucositis," say Arjun Gupta, MD, and Howard (Jack) West, MD, in a Patient Page that accompanies the Clinical Evidence Synopsis.

Dr Gupta is a family physician in Valparaiso, Indiana, and Dr West is a thoracic oncologist at the Swedish Cancer Institute at Swedish Medical Center in Seattle, Washington.

Cryotherapy works by inducing vasoconstriction in connective tissue of the oral mucosa, reducing its exposure to chemotherapy, Dr Treister explained. "Despite our best understanding of the mechanism of oral cryotherapy, it is possible that there are other mechanisms involved," he said.

Cryotherapy probably isn't an option for patients receiving radiation therapy, he added. "Cryotherapy is unlikely to have any benefit as radiation is provided daily over 5 to 7 weeks. Radiation is delivered through the tissue, not via blood vessels, so local vasoconstriction is unlikely to have any physiological or clinical benefit."

When asked whether the Mayo Clinic Cancer Center in Jacksonville, Florida, makes a practice of using oral cryotherapy in patients undergoing radiation therapy, Robert C. Miller, MD, professor of radiation oncology, confirmed, "We do not. Cryotherapy alters drug delivery so it is chemotherapy focused."

More answers are needed, but the fact that a prospective study on the efficacy of oral cryotherapy can't be blinded is an obstacle. It's difficult to "draw conclusions regarding the secondary outcomes of this review, or other chemotherapies," Dr McCabe pointed out.

"This lack of blinding is particularly problematic when the endpoint is the patient's own report of how much pain they feel," Dr Singh said.

Despite the blinding challenge, "the key principles of short half-life and short infusion time must be met," said Dr Treister.

The synopsis authors have disclosed no relevant financial relationships. Dr Treister disclosed that he is director of education for clinical assistance programs, Framingham, Massachusetts. Dr Miller disclosed that he is chairman of the board of directors of Belluscura Ltd and a nonexecutive director of Tekcapital Ltd. Both are in the United Kingdom. Dr Singh has disclosed no relevant financial relationships.

JAMA Oncol. Published online September 1, 2016. Abstract

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