Oral Complications of Cancer Therapy

May 1, 2002

Drs. Sonis and Fey provide a nice description of the problems associated with oral mucositis, information available regarding its etiology, and the cost generated by its treatment.

Drs. Sonis and Fey provide a nice description of theproblems associated with oral mucositis, information available regarding itsetiology, and the cost generated by its treatment.

In their discussion of oral mucositis, the authors present a long list oftheoretical antidotes, many of which offer glimpses of hope that they may beeffective. None of these potential therapies, with one exception, has actuallybeen proven to be helpful in clinical practice. The list of possible antidotesincludes sucralfate, allopurinol, glutamine, pentoxifylline, vitamin E,beta-carotene, azelastine (Astelin), amifostine (Ethyol), misoprostol (Cytotec),benzydamine (Tantum), immunoglobulin, chlorhexidine, povidone iodine,nonabsorbable antibiotic lozenges, keratinocyte growth factor, interleukin(IL)-11, granulocyte colony-stimulating factor (G-CSF [Neupogen]), and oralcryotherapy.

Oral Cryotherapy

The only one of these approaches with proven efficacy is oral cryotherapy(noting that new data regarding keratinocyte growth factor may soon add this tothe "proven efficacy" list). Drs. Sonis and Fey state that"cryotherapy with ice chips seems to be marginally beneficial in patientsbeing treated with [fluorouracil (5-FU)]." They reference one trial thatcompared 30 minutes of cryotherapy with 60 minutes of cryotherapy, as opposed toreferencing one of the two controlled clinical trials that established thebenefit of this therapy. We would like to more definitively state that oralcryotherapy is substantially proven to be efficacious in the prevention ofmucositis related to bolus-dose 5-FU chemotherapy.

The rationale behind this treatment approach is based on the fact that 5-FUhas a short serum half-life (10 to 15 minutes). It was hypothesized that puttingice chips in the mouth 5 minutes before administering a 5-FU bolus injection andcontinuing to do so for 30 minutes would cool the oral cavity and lead tovasoconstriction. The vasoconstriction would hypothetically allow less 5-FU toget to the oral mucosa, thereby hopefully attenuating 5-FU-induced mucositis.

This hypothesis was tested in a late-1980s clinical trial, in which 95patients were randomly assigned to either receive oral cryotherapy or not (thelatter serving as a control group). All patients were receiving bolus 5-dayintravenous 5-FU-based chemotherapy, and none had received prior chemotherapy.Patients randomized to oral cryotherapy placed crushed ice chips in their mouths5 minutes prior to each dose of 5-FU. They were instructed to continuously swishthe ice around in their oral cavities and replenish it before the previousmouthful had completely melted, for a total of 30 minutes. As evaluated bystandard physician grading and patient questionnaires, mucositis was reduced byapproximately 50% in the group receiving oral cryotherapy, compared to thecontrol arm.[1]

Another group independently conducted a trial to confirm or refute thesefindings. This group randomly allocated 84 patients, being treated with 5-FU-containingregimens, to either oral cryotherapy or a control arm.[2] These authors reportedvirtually identical findings, with approximately a 50% reduction in mucositis inthe group receiving the oral cryotherapy.

Another randomized clinical trial evaluated a longer duration of oralcryotherapy. This trial randomized patients to receive oral cryotherapy foreither 30 or 60 minutes. A total of 178 evaluable patients were studied. Theincidence of mucositis was virtually identical in each treatment arm,demonstrating that a longer duration of oral cryotherapy did not provideadditional benefit.[3]

A recently published Cochrane review examined the prevention of oralmucositis in patients receiving chemotherapy.[4] The review looked at 38 reportsthat included 27 usable studies and concluded that, of eight prophylacticregimens studied, oral cryotherapy was the only one that appeared to beeffective, with a 0.57 relative risk of subsequent mucositis.

Recently obtained pilot information suggests that oral cryotherapy might alsoreduce oral mucositis related to a newer agent, edatrexate, which has a shortserum half-life, similar to 5-FU.[5-7] These data, however, are based onnonrandomized studies.


Finally, let us comment on Drs. Sonis and Fey’s discussion of the treatmentof xerostomia. The use of pilocarpine (Salagen) and amifostine has shown modestbenefits in xerostomia. When administered intravenously, amifostine can beproblematic, often causing hypotension, nausea, and vomiting. A recent studyshowed that, when used subcutaneously, amifostine produces similar improvementsin xerostomia with fewer side effects.[8]

In addition to the potential benefits of amifostine and pilocarpine, a recentsmall pilot trial suggested that acupuncture may be helpful inpilocarpine-resistant xerostomia following radiation therapy for head and neckcancer.[9] Follow-up evaluations 1 month after treatment suggested markedimprovement in patients who received acupuncture. Although this soundspromising, further work is necessary to confirm or refute the efficacy ofacupuncture in this clinical situation.


1. Mahood DJ, Dose AM, Loprinzi CL, et al: Inhibition of fluorouracil-inducedstomatitis by oral cryotherapy. J Clin Oncol 9(3):449-452, 1991.

2. Cascinu S, Fedli A, Fedli SL, et al: Oral cooling (cryotherapy), aneffective treatment for the prevention of 5-fluorouracil-induced stomatitis(Part B). Eur J Cancer 30B(4):234-236, 1994.

3. Rocke LK, Loprinzi CL, Lee JK, et al: A randomized clinical trial of twodifferent durations of oral cryotherapy for prevention of 5-fluorouracil-relatedstomatitis. Cancer 72(7):2234-2238, 1993.

4. Clarkson JE, Worthington HV, Eden OB: Prevention of oral mucositis or oralcandidiasis for patients with cancer receiving chemotherapy (excluding head andneck cancer). Cochrane Database of Systematic Reviews 2:CD000978, 2000.

5. Edelman MJ, Gandara DR, Perez EA, et al: Phase I trial of edatrexate pluscarboplatin in advanced solid tumors: Amelioration of dose-limiting mucositis byice chip cryotherapy. Invest New Drugs 16(1):69-75, 1998.

6. Gandara DR, Edelman MJ, Crowley JJ, et al: Phase II trial of edatrexateplus carboplatin in metastatic non-small-cell lung cancer: A SouthwestOncology Group study. Cancer Chemother Pharmacol 41(1):75-78, 1997.

7. Dreicer R, Propert KJ, Kuzel T, et al: A phase II trial of edatrexate inpatients with advanced renal cell carcinoma. An Eastern Cooperative OncologyGroup study. Am J Clin Oncol 20(3):251-253, 1997.

8. Koukourakis MI, Kyrias G, Kakolyris S, et al: Subcutaneous administrationof amifostine during fractionated radiotherapy: A randomized phase II study. JClin Oncol 18(11):2226-2233, 2000.

9. Niemtzow RC, May BC, Peng YP, et al: Acupuncture technique forpilocarpine-resistant xerostomia following radiotherapy for head and neckmalignancies. Med Acupunct 12:42-43, 2000.