Antunes, H.S., Herchenhorn, D., Small, I.A., Araujo, C. M., Viegas, C.M.P., de Assis Ramos, G., . . . Ferreira, C.G. (2017). Long-term survival of a randomized phase III trial of head and neck cancer patients receiving concurrent chemoradiation therapy with or without low-level laser therapy (LLLT) to prevent oral mucositis. Oral Oncology, 71, 11–15.
To compare between LLLT and placebo for overall disease-free survival (DFS) and progression-free survival (PFS) of patients with head and neck cancer who received chemoradiation therapy. Randomized double-blinded placebo controlled phase III trial
Patients received low-level laser therapy or placebo; LLLT with an InGaAIP diod (660 nm to 100 mW-1 J-4J/cmsq, and a spot size of 0.24 cm2 five days a week before radiotherapy. contact with the mucosa on nine points per region for 10 seconds per point, totaling 12 minutes per patient for LLLT.
PHASE OF CARE: Active anti-tumor treatment
Randomized phase III trial of patients with head and neck cancer. Details of randomization not provided.
Both group received treatments of chemotherapy (cisplatin 100 mg/m2 at day 1, 22, and 43) and radiotherapy according to tumor localization, using megavoltage radiotherapy with 2D and 3D techniques. A total dose of 70.2 Gy daily in 39 fractions, five days a week, using a cobalt-60 and a linear accelerator unit.
The adverse effects were evaluated daily, according to the Common Toxicity Criteria, version 3.0, from the National Cancer Institute (NCI-CTC) [16]. Oral mucositis was evaluated every day during the treatment period, according to the OMS and OMAS scales. The modified visual analog scale was used to evaluate pain. Body weight (body mass index) was measured every week. Patients were evaluated by a complete physical examination, oroscopy, nasopharyngoscopy, hematologic and biochemical profiles, chest radiography, and CT/MRI performed every four months for the first two years, every six months from the third to the fifth year, and then annually according to the RECIST criteria.
* statistically significant findings.
Laser group had better progression-free survival and complete response, however this did not carry over to overall survival significance. Oral mucositis severity was statistically significantly lower in LLLT group.
LLLT was beneficial to reduce oral mucositis. No statistically significant results for overall survival is likely affected by type II error (small sample size), and larger sample size study is needed. This study found statistically significant improvement for progression-free survival and LLLT may improve not only mucositis occurrence/severity but also patients’ survival.
Zheng, B., Zhu, X., Liu, M., Yang, Z., Yang, L., Lang, J., . . . Zhu, G. (2018). Randomized, double-blind, placebo-controlled trial of Shuanghuabaihe tablets to prevent oral mucositis in patients with nasopharyngeal cancer undergoing chemoradiation therapy. International Journal of Radiation Oncology, Biology, Physics, 100, 418–426.
To evaluate if Shaunghaubaihe tablets can prevent oral mucositis for patients with locally advanced nasopharyngeal carcinoma undergoing chemoradiotherapy.
Multi-site, randomized, double blind study of Shuanghuabaihe tablets versus placebo (four tablets, three times a day) started at the initiation of chemoradiotherapy and lasting seven weeks. Patients could stop taking the tablets if grade 3 mucositis developed.
PHASE OF CARE: Active anti-tumor treatment
RCT. Patients age 18-70 years with locally advanced nasopharygeal carcinoma randomly assigned to receive Shaunghaubaihe tablets or a placebo, starting at the initiation of chemoradiation.
The incidence of different stages of mucositis was compared using Fisher’s exact test and the 95% confidence intervals. The Kaplan-Meier method was used to estimate the median time of the occurrence of OM (latency). To compare latency, the Cox proportional hazard model was used for hazard ratio (HR) and 95% CI values. One-way ANOVA and Fisher’s exact were used to compare toxicities and secondary efficacy endpoints. All data was analyzed using SAS, version 9.2, software.
Shaunghaubaihe tablets significantly reduced the incidence, latency, and severity of oral mucositis in patients with nasopharyngeal cancer.
Two patients from placebo and eight from treatment arm did not complete the entire course of radiation therapy. This is an initial study and further clinical study is needed to evaluate and verify therapeutic effects.
Therapeutic agents that prevent oral mucositis are needed because systemic oral care alone is insufficient.
Wang, C., Wang, P., Ouyang, H., Wang, J., Sun, L., Li, Y., . . . Pan, Z. (2017). Efficacy of traditional Chinese medicine in treatment and prophylaxis of radiation-induced oral mucositis in patients receiving radiotherapy: A randomized controlled trial. Integrative Cancer Therapies, 17, 444–450.
To estimate the efficacy of traditional Chinese medicine (Chining decoction, CHIN) for radiation-induced oral mucositis in patients with head and neck cancer.
70 consecutive patients were randomly assigned to receive CHIN (treatment group) or recombinant human epidermal growth factor (rhEGF) spray (control group) at a 1:1 ratio in the period between May 2014 to December 2015. CHIN was administered to treatment group from the first day of radiotherapy until the completion of radiotherapy. Simultaneously, the rhEGF spray was administered to control group on the oral mucosa of the irradiated area. The clinical benefit was determined by gradation of mucositis (Common Terminology Criteria for Adverse Events, version 4.0), oral pain, and xerostomia (visual analysis scale) for each week during radiotherapy. Body mass index was evaluated before and after radiotherapy.
PHASE OF CARE: Active anti-tumor treatment
Prospective control randomized trial
CHIN presented an obvious advantage in preventing radiation-induced oral mucositis compared with rhEGF spray.
Marucci, L., Farneti, A., Di Ridolfi, P., Pinnaro, P., Pellini, R., Giannarelli, D., . . . Sanguineti, G. (2017). Double-blind randomized phase III study comparing a mixture of natural agents versus placebo in the prevention of acute mucositis during chemoradiotherapy for head and neck cancer. Head and Neck, 39, 1761–1769.
To test the effectiveness of four natural compounds (propolis, aloe vera, calendula, and chamomile) in the prevention of acute mucositis during chemoradiotherapy for head and neck cancer.
The patients were randomized to receive a mixture of the natural ingredients or placebo. All patients received dental and nutritional evaluations and were allowed to use standard supportive care such as baking soda mouth rinses, NSAIDs, opioids, and IV hydration. The placebo had the same volume, color, flavor, and density as the experimental solution. The pharmacist who dispensed the study drugs managed the randomization list. Patients were instructed to rinse with 7 ml four times per day (before each meal and RT) during weekdays and before each meal (three times per day) on weekends. Weekly interviews were conducted along with a physical examination, including visual inspection of the oral cavity and the oropharynx, by a nurse and a radiation oncologist. Body weight, objective mucositis, pain control, and dysphagia were assessed during these visits.
PHASE OF CARE: Active anti-tumor treatment
Phase III double-blind randomized placebo controlled; 1:1 experimental versus control
CTCAE, version 3.0, was used for grading mucositis. The Verbal Descriptor Scale was used for assessing pain. Locoregional control and OS were computed with the Kaplan-Meier method from the last day of treatment and comparison was done with the log-rank test (These were included in the secondary endpoints of the study).
No difference was noted between arms.
The prophylactic use of the natural agent combination, propolis, aloe vera, calendula, and chamomile, did not show a benefit versus placebo in the prevention of oral mucositis for patients with head and neck cancer receiving chemoradiotherapy.
This was a well-conducted single-site clinical trial.
Use of natural ingredients for supportive care in oncology is usually preferable to more expensive, hard to access pharmacologic interventions. However, if the evidence does not support their use, even natural ingredients should not be used due to potential increase costs and untoward effects. Nurses play an important role in patient and HCP education about evidence-based interventions.
Mazzola, R., Ricchetti, F., Fiorentino, A., Giaj-Levra, N., Fersino, S., Tebano, U., . . . Alongi, F. (2016). Fentanyl pectin nasal spray for painful mucositis in head and neck cancers during intensity-modulated radiation therapy with or without chemotherapy. Clinical and Translational Oncology, 19, 593–598.
To evaluate the effect and toleration of transmucosal opioid for painful mucositis affecting swallowing.
Retrospective medical chart review was done for data collection for individuals who had opioid maintenance and received fentanyl pectin nasal spray for incidental mucositis pain. Results in patients were compared at different time points when they did and did not use fentanyl pectin nasal spray for incidental breakthrough pain.
PHASE OF CARE: Active anti-tumor treatment
Retrospective observational
After implementation of transmucosal opioid for incidental pain, oral intake improved (p = 0.000). With use of fentanyl pectin nasal spray, intensity of breakthrough pain episodes went from 5.73 (SD = 1.54) to 2.25 (SD = 2.45).
Transmucosal opioids may be helpful in managing incidental pain associated with mucositis, and may facilitate oral nutritional intake.
Due to rapid onset, transmucosal opioid use for incidental pain that interferes with swallowing and oral intake in patients with head and neck cancer may be of benefit. Further well-designed research in this area is warranted.
Chitapanarux, I., Tungkasamit, T., Petsuksiri, J., Kannarunimit, D., Katanyoo, K., Chakkabat, C., . . . Traisathit, P. (2018). Randomized control trial of benzydamine HCl versus sodium bicarbonate for prophylaxis of concurrent chemoradiation-induced oral mucositis. Supportive Care in Cancer, 26, 879–886.
To compare the efficacy of benzydamine HCl with sodium bicarbonate in the prevention of concurrent chemo rt-induced OM in patients with head and neck cancer.
Sixty locally advanced patients with head and neck cancer treated with high-dose RT concurrently with platinum-based chemotherapy were randomly assigned to receive either benzydamine HCl or sodium bicarbonate from the first day of treatment to two weeks after completion of treatment.
RCT with two intervention groups
Patients were evaluated by the radiation oncologists at baseline before CCRT, weekly during CCRT, at the end of CCRT, and at four weeks after CCRT. The Oral Mucositis Assessment Scale (OMAS) was used to assess severity of mucositis. Ulceration score was 0 for no lesion, 1 for lesion less than 1 cm2, 2 for lesion 1–3 cm2, and 3 for lesion more than 3 cm2. Erythema score was 0 for no lesion, 1 for mild to moderate erythema, and 3 for severe erythema. Pain score (0–10), all prescribed medications including analgesic, artificial saliva supplement, and anti-infection medications, the need for hospitalization, treatment interruption, and the addition of nutritional support or feeding tube were also recorded. Oral candidiasis assessment was based on the physical examination of pseudomembranous lesions or angular cheilitis in centers except at CMUH center where confirmation by microscopic identification of Candida was used.
Prophylaxis rinsing with benzydamine HCl can be more effective in reducing severity of OM induced by CCRT, when compared to basic care with sodium bicarbonate mouthwash. Median of OMAS scores at weekly assessment during CCRT was lower in benzydamine HCl group compared to control. In both groups, maximum of third quartile of OMAS scores around fifth to seventh week of CCRT. Scores decreased at four weeks after CCRT. Statistically, median for OMAS scores was significantly lower in study group at every week between second and eighth week of CCRT. The corresponding p values for those weeks in chronological order were 0.003, < 0.001, < 0.001, < 0.001, < 0.001, 0.01, and 0.04. Maximum of third quartile of OMAS scores to be around fifth to sixth week in both groups. Maximum OMAS score across whole period of CCRT in benzydamine HCl group was 25, lower than maximum of 37 in sodium bicarbonate group. No significant difference in median of pain scores between two groups during CCRT and at follow-up. Corresponding p values from second to eighth week were 0.88, 0.59, 0.96, 0.73, 0.63, 0.92, and 0.15 and p value at follow-up after CCRT was 0.8. Maximum of third quartile of pain scores at seventh week of CCRT in study group and eighth week in control group. Maximum pain score across period of CCRT was 10 in both groups. Four weeks after CCRT, median of pain score decreased to 2 in both groups. Poor compliance was defined as patients in postoperative CCRT group and in definitive CCRT group who received weekly chemotherapy less than 3 cycles and 4 cycles, respectively. More patients with poor compliance in control group than in study group (i.e., 13 patients versus 10 patients). No differences were found between the two groups. Most patients in both groups need analgesic drugs; 89% in control group and 90% in study group, p value = 1. The most common analgesic drugs used were opioids (syrup morphine/morphine sulfate tablet; MST/morphine sulfate sustain released; kapanol®), prescribed usage rates were 48% in control group and 33% in study group. For antifungal agents, none in benzydamine HCl group needed them, whereas 19% of patients in sodium bicarbonate group required nystatin oral suspension or clotrimazole tablet. Rate of feeding tube placement was same in both groups during CCRT (i.e., 24 and 22% in the study group and the control group, respectively). Oral retention and compliance for mouthwash products were better in sodium bicarbonate arm than in benzydamine HCl arm. Four patients (6.75%) in study arm could not tolerate full dose of benzydamine HCl due to burning and stinging sensation. For these patients, mouthwash was diluted at 1:1 with water.
Prophylaxis oral rinsing with benzydamine HCl for patients undergoing high-dose radiotherapy concurrently with platinum-based chemotherapy was superior to sodium bicarbonate mouthwash in terms of alleviating the severity of oral mucositis and encouraging trend for reducing the need of oral antifungal agents use.
Review prophylaxis and acute treatment protocol practices.
Weissheimer, C., Curra, M., Gregianin, L.J., Daudt, L.E., Wagner, V.P., Martins, M.A.T., & Martins, M.D. (2017). New photobiomodulation protocol prevents oral mucositis in hematopoietic stem cell transplantation recipients--A retrospective study. Lasers in Medical Science, 32, 2013–2021.
The aim of this study was to evaluate the effect of photobiomodulation (PBM) in reducing the incidence and severity of OM in patients undergoing HSCT, comparing two protocols that differ only in session frequency, either daily or three times a week.
PBM applied three times per week versus seven times per week in patients undergoing HSCT
A retrospective study was to evaluate the preventive effect of PBM applied three times per week versus seven times per week in patients undergoing HSCT.
Differences between groups were evaluated using the chi-square test or Fischer’s exact test for qualitative data and the Mann-Whitney test for quantitative data. Receiver operating characteristic (ROC) curves were constructed to analyze the sensitivity and specificity of quantitative risk factors in predicting the presence or absence of OM. The area under the curve is a measure of test accuracy. The SPSS for Windows software package, version 18.0, was used to perform these statistical analyses. Two-way analysis of variance (ANOVA) was used to compare OM average between groups, and the t test was used to compare the average OM at each point.
PBM was effective in preventing OM in patients undergoing HSCT even when it was applied three times a week. Both PBM protocols were equally efficient in preventing OM (p = 0.34, ANOVA).
Independent of the PBM protocol used, patients who received allogeneic transplant (p < 0.01, Fischer’s exact test), total body irradiation (TBI, 12 Gy) (p = 0.01, chi-square test), busulfan plus cyclophosphamide (p < 0.01, chi-square test), or methotrexate-containing regimens (p < 0.01, Fischer’s exact test) demonstrated higher OM incidence and severity. Myelosuppression (p < 0.01, Mann-Whitney test) and impaired renal function (p = 0.02, Mann-Whitney test) were also considered risk factors for OM.
The study indicates that PBM is effective in preventing OM in patients undergoing HSCT even when administered three times a week.
OM is frequently seen side effect of patients receiving HSCT, these lesions impact patient quality of life, controlling this condition is extremely important, and developing effective interventions is a high priority in protocol support among patients with cancer.
Cabrera-Jaime, S., Martinez, C., Ferro-Garcia, T., Giner-Boya, P., Icart-Isern, T., Estrada-Masllorens, J.M., & Fernandez-Ortega, P. (2018). Efficacy of Plantago major, chlorhexidine 0.12% and sodium bicarbonate 5% solution in the treatment of oral mucositis in cancer patients with solid tumour: A feasibility randomised triple-blind phase III clinical trial. European Journal of Oncology Nursing, 32, 40–47.
To evaluate/compare three treatments for oral mucositis: (1) Plantago major extract mouthwash, (2) chlorhexidine 0.12%, and (3) aqueous solution of 5% sodium bicarbonate for the treatment of oral mucositis in patients with solid tumors. Evaluation points included healing time, pain, oral intake, and quality of life.
Randomized controlled trial (phase 3)
The treatment was 14 days for all groups. All groups received education regarding the management of mucositis, a set of instructions, a diary to record signs and symptoms of mucositis, and instruction for proper storing of the mouthwashes. All participants were instructed to rinse with 8 ml of solution for two minutes every six hours. They were instructed to leave 15 minutes between the two mouthwashes.
Randomized controlled trial; investigators, participants, care providers, and statistician were all blinded.
In this small group, there is no advantage in using a chlorhexidine or Plantago major extract mouthwash in comparison to a double sodium bicarbonate solution. The latter is likely less expensive and more readily available
This study does not support the use of Plantago major or chlorhexidine mouthwashes over double doses of sodium bicarbonate 5% aqueous solution.
Aghamohammadi, A., Moslemi, D., Akbari, J., Ghasemi, A., Azadbakht, M., Asgharpour, A., & Hosseinimehr, S.J. (2018). The effectiveness of Zataria extract mouthwash for the management of radiation-induced oral mucositis in patients: A randomized placebo-controlled double-blind study. Clinical Oral Investigations, 22, 2263–2272.
Primary: To evaluate the use of Zataria multiflora (ZM) extract mouthwash to reduce the incidence and severity of oral mucositis (OM) in adult patients with head and neck cancer undergoing radiation therapy alone or combined radiation and chemotherapy.
Secondary: The impact of ZM extract mouthwash on the amount of opioid used, the use of anti-inflammatory drug use, antibiotic use, and body weight over the course of therapy
Double blinded, randomized, placebo controlled study
Primary outcomes:
Secondary outcomes:
The use of ZM mouthwash positively impacted the incidence and severity of OM in patients with head and neck cancer undergoing head and neck radiation with or without concurrent chemotherapy. In addition, the ZM mouthwash contributed to less use of opioid analgesia, less antibiotic use, and decreased weight loss.
ZM may offer an option for decreasing OM in patients undergoing radiation with or without concurrent chemotherapy in the head and neck cancer population.
Ramirez-Amador, V., Anaya-Saavedra, G., Labardini-Mendez, J., & Ponce de Leon-Rosales, S. (2018). Double-blind placebo-controlled randomized clinical trial evaluating doxycycline effects on chemotherapy-induced oral mucositis. Journal of Clinical Pharmacy and Therapeutics, 43, 202–208.
PURPOSE: To use sub-antimicrobial doxycycline 50 mg per day on patients with leukemia to reduce the onset and severity of OM
TYPES OF PATIENTS ADDRESSED: Patients with ML or LL
RESOURCE TYPE: Evidence-based guideline
PROCESS OF DEVELOPMENT: Patients aged 15 years and older with specific leukemia (N = 47). Patients had basic oral examination and were taught oral care protocol. A baseline oral examination was done three times per week for three weeks. The strategy of development was to prevent the devastating consequences of OM in patients with leukemia.
INCLUSION CRITERIA: Aged 15 years or older, male or female
EXCLUSION CRITERIA: Patients using the following medications: acitretin, isotretinoin, or tretinin
The low-dose use of doxycycline proved ineffective in the management of OM in patients with acute leukemia during chemotherapy.
Effectiveness unlikely. The intervention with doxycycline lacks effectiveness in the reduction of the severity or onset of OM in patients with leukemia.
The findings are not generalizable; limited to one disease group.
The nursing implication is that continued attention to OM is needed to manage and treat the dose interruption and debilitating nutritional problems associated in patients receiving treatment for cancer.