Low Level Laser Therapy in Patients Undergoing Hematopoietic Cell Transplantation

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Pediatrics, elder care

The primary outcome (overall severity of oral mucositis) of this analysis was that prophylactic LLLT reduced the overall risk of severe mucositis when compared to a placebo or no therapy (RR = .37, 95%, CI = .18–.67, p = .001). The absolute risk reduction was -.35 (95%, CI = -.48– -.2, p < .0001). Secondary outcomes included a decreased risk of severe mucositis at the time of expected worst severity with prophylactic LLLT (RR = .34, 95%, CI = .20–.59, p = .0001). Overall mean grade of mucositis: standardized mean difference = -1.49, 95%, CI = -2– -.95;=, p < .0001. Duration of severe (grade 3 or 4) mucositis: weighted mean difference = -5.32, 95%, CI = -9.45– -1.19, p = .01. Incidence of pain: RR = .89, 95%, CI = .76–1.04, p = .15. Incidence of severe pain: RR = .26, 95%, CI = .18–.37, p < .0001. Overall mean pain score: WMD = -2.46, 95%, CI = -4.4– -.77, p = .004. Number of patients needing opioid analgesia: RR = .47, 95%, CI = .37–.60, p < .0001. Unplanned interruption in radiation (from mucositis in patients with head and neck cancer): RR = .23, 95%, CI = .12–.44, p < .0001.

The overall risk of severe mucositis is decreased by the use of low-level laser therapy. The duration of mucositis, the risk of severe pain, the need for opioid analgesia, and radiation treatment interruption also is positively impacted by LLLT.

There is heterogeneity to the laser schedules, mucositis assessment scales, laser parameters, intervals, and time points for assessment and outcome reporting (per the authors). It is difficult to generalize this study to the pediatric population. The feasibility of using laser therapy continues to be an issue in nursing.

Prophylactic LLLT shows benefit in the prevention of oral mucositis. Additional research to delineate the feasibility of this intervention and define best practice is needed.

Low-power laser therapy (LPLT) versus placebo

Only dentists knew the randomization.

Low level intensity laser: InGaAIP diode laser—660 nm, 46.7 mW

Predental care

Oral care: Extrasoft toothbrushes; dental paste with a peroxidase system after meals, and alcohol-free chlorhexidine solution until neutrophil recovery TID

Evaluations were performed daily by one dentist (not blinded) and three nurses (blinded).

Crossover allowed for control group patients who developed grade 4 oral mucositis.
 

The sample was comprised of 38 patients with HSCT.

Adults M =36.5/36.8

Women = 7/8
Men = 12/11

Autologous HSCT = 5/5

Allogenic HSCT = 14/14
 

Centro de Transplante de Medula Ossea

January 2004-May 2005

Randomized, placebo-controlled, quantity and prospective clinical trial

WHO scale

OMAS

VAS
 

All patients completed the study; none were lost to follow-up or excluded.

LPLT less intense oral mucositis
Grade 0 = 1, 63.2%, 12 of 19 versus 10.5%, 2 of 19 (p < 0.001)

6 LPLT, 31.5% WHO Grade 2

94.7% WHO 0–2

Control group was the opposite (data not provided) (p < 0.001).

Mucositis-free survival hazard ration grade 2, 3, and 4 was 0.41 (p = 0.002); the hazard ration grade for grade 3 and 4 was 0.07.

OMAS = 84.2% (16) patients receiving laser treatment stayed on a weighted average zone of 0–2.9 versus 26.3% (5) (p = 0.007).

Patients receiving laser treatment presented with small extension of ulcerous area (p = 0.003).

Control group showed mucositis earlier (D + 5) than laser group (D + 6) (p = 0.67, NS).

Longer duration 6 versus 9 (p = 0.13, NS)

Longer to heal (p = 0.15)
 

No differences in presence and intensity of pain

No differences in blood cultures

The level of agreement among evaluators was 81.7%.

Sample size

Implies difference when p value is not significant

Narrative frequently does not match p values.
 

780 nm 60 mW 4 J/cm² was applied uniformly to five areas of the oral cavity for five consecutive days from initiation of chemotherapy.

The sample was pediatric patients (some with HSCT) receiving a variety of chemotherapies.

Laser group: n = 29
Control group: n = 31
 

The study ran from May 2003-February 2005.

RCT was the study design.

CTC-NCI
Nutritional Status Assessment
Day 8,15
 

Day 8 results: 13 patients in the laser group and 7 patients in the control group with mucositis; median grade of mucositis was 2 for the laser group and 1 for the control group (p = 0.234)

Day 15 results: 13 patients in the laser group and 11 patients in the control group with mucositis; median grade of mucositis was 1 in both groups; prevalence and severity were similar (p = 0.208)
 

Almost identical prevalence of mucositis and other findings; no evidence to support laser for prevention

Rigorous oral care may have masked results.

Optimal timing of laser treatment is unknown.

Small sample
 

Prophylactic laser treatment was administered daily from beginning of conditioning regimen to two days after stem cell transplantation.

Patients received gallium aluminum arsenate diode laser therapy on four anatomic sites of the oral mucosa.

660 nm 10 mW 2.5 J/cm² was administered. Each anatomic site was illuminated for 10 seconds per point.

 

Patients with HSCT from Brazil aged 17-62 years

Historical control group (1999–2000): n = 25

Laser group: n = 24
 

The study occurred from January 2003-September 2004.

WHO

Administration of morphine

Time of parenteral nutrition
 

Incidence of mucositis was the same in both groups.

Percentage of grade 2, 3, and 4 mucositis was less in laser group, not SS (p = 0.12). The laser group took longer to develop grade 1 (4.36 versus 6.12 days [p = 0.01], had fewer days of pain (5.64 versus 2.45 [p = 0.04], and had fewer patients who required morphine (10 versus 4 [p = 0.07].
 

Limited sample size and methodology

Number of patients with grade 3–4 may have been SS with larger sample.
 

To evaluate the frequency and evolution of oral mucositis (OM) among stem cell transplant recipients subjected to therapeutic laser versus mucositis formula

Patients (n = 22) were randomly assigned to control or low level laser therapy (LLLT) daily. The treatment phase for both groups began with the initial clinical manifestations of mucositis with follow up until day +15 after transplant. Two types of laser were used on alternate days, one indicated for tissue repair and the other for analgesia.

• The study reported on 22 patients with a mean age of 27.5–32.7 years.
• The sample was 23% female and 77% male.
• Patients had hematologic malignancies and were receiving the myeloablative conditioning regimen and allogeneic stem cell transplant.
• All patients were given preventive treatment consisting of soft-bristled toothbushes and saline rinses four times daily followed by benzidamine solution, which was replaced with a 0.12% chlorhexidine gluconate solution toward the end of the study.
• The control group received the standard of care with the mucositis formula (antiinflammatory [benzidamine], antifungal [nistatin], and anesthetic [neututocain] with distilled water).

This was a single-site conducted in the bone marrow transplant unit (BMTU) of the University Hospital School of Medicine of Ribeirao Preto (UHSMRP) at the University of São Paulo in Brazil.

The study was a randomized controlled trial.

• The World Health Organization (WHO) Oral Toxicity Scale and Oral Mucositis Assessment Scale (OMAS) were used.
• Patients in the laser group completed questionnaires about laser therapy.

The laser treatment group had lower frequency of oral mucositis (p = 0.02) and a lower mean grade of mucositis (p < 0.01).

The inclusion of LLLT was effective in lowering the frequency and treating oral mucositis in patients being treated with high dose myeloablative chemotherapy in preparation for stem cell transplant.

• The sample size was small with fewer than 30 patients.
• The control group did not receive sham treatment, so the study was not blinded.
• Authors did not describe the areas that were treated with lasers.

Laser therapy is effective in the treatment of mucositis, but it is very high tech and requires special equipment and highly trained personnel.

To evaluate the efficacy of low level laser therapy (LLLT) for the treatment of chemotherapy-induced oral mucositis (OM) in pediatric patients undergoing chemotherapy or stem cell transplant

Children and adolescents with cancer receiving chemotherapy or hematopoietic stem cell transplantation (HSCT) who developed grade II OM were included. OM was scored daily by the same investigator. In the experimental group, the treatment was applied to each OM lesion for five consecutive days. The control group received sham treatments to each OM lesion for five consecutive days also.

• The study reported on 14 patients with an age range of 4.8–12.3 years.
• The sample was 19% female and 81% male.
• The sample had three patients diagnosed with solid tumors, 15 patients with lymphoma/leukemia, and three patients undergoing stem cell transplant.

This was a single site, inpatient study conducted in the Pediatric Oncology Unit of the Hospital de Clinicas de Porto Alegre at Federal University of Rio Grande do Sul, Brazil.

The study was a randomized, placebo-controlled trial.

• The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 2.0 was used.
• One examinator assessed mean, standard deviation, and percentiles for age, localization and grade of mucositis, and mucositis severity daily.

No differences were found in grades of mucositis as a function of the LLLT protocol. Mucositis was diagnosed 5.0 to 7.5 days postchemotherapy. On the seventh day after the diagnosis of mucositis, 1 out of 9 patients in the laser group and 9 out of 12 patients in the sham group had grade II or greater OM (p = 0.029). The mean OM duration in the laser group as compared to the sham group was 3.1 days less (p = 0.004).

LLLT can significantly reduce the duration of chemotherapy-induced OM in children.

• The sample size was small with fewer than 30 patients.
• The study did not evaluate pain or functional impairment.

Laser therapy is effective in treatment of mucositis, but it is very high tech and requires special equipment and highly trained personnel.

Low level laser therapy (LLLT) using two different low level GaAIAs diode lasers was administered 650 nm to group I and 780 nm to group II compared to sham treatment in the placebo group (group III) beginning on the first day of conditioning and continuing through two days after HCT.

Assessors and patients were blinded; only the laser therapist knew the treatment type.

Powered for 22 subjects per group

70 patients were treated on protocol.

Group 1: n = 23
Group 2: n = 24
Group 3: n = 24


The median age was 44–48 years (range = 18–69 years).

Autologous versus allogeneic was 17% versus 82% in group I, 9% versus 90% in group 2, and 8% versus 92% in group III.
 

February-November 2001

Randomized, double-blind, placebo-controlled study of patients with HCT

Oral mucositis index OMI and VAS for pain

0, 4, 7, 11, 14, 18, 21
 

State mean OMI scores varied most at day 11. Scores approached significance (p = 0.06 not significant) when adjusted. Patient-specific average OMI scores for TBI were p = 0.03 (group I) and p = 0.23 (group II).

Two patients died with severe mucositis.
 

Patients in the placebo group appeared to have suffered more pain than patients in the laser treatment group, particularly group I.

The study demonstrated a tendency for LLLT to reduce severity of mucositis during the second week.

Pain data were incomplete; some patients were too ill to do VAS.

Although randomly assigned, TBI and busulfan/cytoxan were not equally distributed.

Small sample size

Set up as a prevention trial, so treatment only occurred through day 2.
 

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

• Patients received three PBM sessions weekly (on Monday, Wednesday, and Friday). PBM was applied using a continuous-wave diode laser (0.24 J total radiant energy per point, 33 points)
• Patients received daily PBM sessions. PBM was applied using the same continuous-wave diode laser at the same settings used for group I (0.24J total radiant energy per point, 33 points)
• There is a slight difference in the power outage of each intervention as well as exposure time.

• N = 99
• AGE: 13 to 71 years
• MALES: 51.5%
• FEMALES: 48.5%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: OM
• OTHER KEY SAMPLE CHARACTERISTICS: Allogeneic HSCT, autologous HSCT

• SITE: Single site    
• SETTING TYPE: Inpatient  (not specifically  identified)
• LOCATION: Porto Alegre Clinical Hospital

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS:  Pediatrics, elder care, palliative care

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.

• Small sample (< 100)
• Intervention expensive, impractical, or training needs (The cost of bringing in a professional or asking the patient to go to a dental office was a hindrance.)
• Other limitations/explanation: Retrospective nature of the study. Allo versus auto transplant regimens are different treatment paths especially the chemotherapy regimens that could influence toxicities.

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.

570 articles were included in this literature review. Literature contained prevention and/or treatment methods for mucositis. Interventions for treatment of mucositis were given, recommendations against an intervention were provided, suggestions in favor of an intervention were supplied, and suggestions against an intervention were given.

Recommendations included a combination of teeth brushing, flossing, mouth rinsing, and use of growth factors and cytokines in treatment of mucositis. The use of anti-inflammatory agents was also recommended. Low level laser therapy was recommended in prevention of mucositis with specific types of cancer treatment. Cryotherapy was also recommended for patients receiving chemotherapy. A list of natural and miscellaneous agents was recommended for treatment and prevention of mucositis.

Limitations of this study include clinical situations that were not seen in the literature review or that are rare in clinical settings. These limitations occur because of conflicting evidence or not enough evidence provided.

Nurses should be assessing patients' pain control, nutritional support, ability to eat, and oral hygiene practices, and should be teaching on the use of oral care products that are essential for prevention.

To review available literature to develop guidelines for the use of laser and other light therapies in patients with cancer

• This review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO).
• Database searched was MEDLINE.
• Search keywords were oral mucositis OR stomatitis AND lasers, laser, low level laser therapy (LLLT), light therapy, phototherapy, light-emitting dioide, visible light, and infrared.

• Patients were in the active antitumor treatment phase of care.
• The study has clinical applicability for pediatric applications.

A total of 692 papers initially were identified, and 24 clinical trials were included in the final review.

• Recommendations were laser therapy in a wavelength around 650 nm, intensity of 40 mW, and treatment of each square cm to tissue energy dose of 2 J/cm³ for prevention of oral mucositis in patients undergoing hematopoietic cell transplantation (HCT). For laser therapy as treatment, no guideline was possible because of insufficient evidence.
• No guidelines for LED and other light sources were provided because of insufficient evidence at the time, but promising findings noted that LED and visible light therapy appeared to interact with human tissue in the same way as LLLT.
• Laser therapy was recommended for prevention of radiation-induced oral mucositis in patients without concomitant chemotherapy with head and neck cancer.
• No guidelines were possible for combination radiation and chemotherapy because of inconsistent findings.
• No guideline were possible for other groups of patients.

• Multiple sources of evidence were relatively flawed studies.
• The authors noted later-breaking evidence that is promising in other groups but not fully included in the review.
• The review included articles through 2010 only.

Guidelines support use of LLLT for the prevention of oral mucositis in patients undergoing HCT and in patients with head and neck cancer receiving radiotherapy. The research in this area involves a variety of laser devices, protocols, and dosage, making it difficult to identify a specific protocol for clinical application. The most effective wavelengths and dosages are not yet clear. Most protocols examined have involved daily and long treatment times.  Based on accumulating evidence, LLLT or other forms of light therapy have the potential to become part of routine treatment.

To summarize the evidence around the use of radiotherapy, standard-dose chemotherapy, and high-dose chemotherapy with or without total body irradiation plus hematopoietic stem cell transplantation (HSCT) for the management of mucositis

• Databases searched were the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO).
• Evidence was evaluated based on the American Society of Clinical Oncology (ASCO) Levels of Evidence (I-V) and Grades of Recommendation (A-D). Statements without grading were considered justified standard clinical practice by the expert authors and the European Society for Medical Oncology (ESMO) faculty.

• Institutions should develop oral care protocols based on clinical practice and interdisciplinary involvement. Staff and patient education are essential. Basic oral care should include saline mouth rinses 4–6 times per day and use of a soft toothbrush replaced on a regular basis. 
• Patient-controlled analgesic (PCA) with morphine is recommended for the treatment of pain in patients with oral mucositis undergoing HSCT.
• Regular oral pain assessment and topical anesthetics can provide short-term pain relief. 
• Chlorhexidine rinses are not recommended to treat established mucositis but may be an option to enhance treatment of oral infection.
• Benzydamine oral rinse is recommended for prevention of mucositis in patients with head and neck cancer receiving radiotherapy.
• For prevention of mucositis in patients receiving standard-dose chemotherapy,
  • Oral cryotherapy for 30 minutes is recommended in patients receiving fluorouracil (5-FU).
  • Keratinocyte growth factor-1 (palifermin) 40 mcg/kg per day for three days may be useful in patients receiving bolus 5-FU plus leucovorin.
• For prevention of mucositis in patients receiving high-dose chemotherapy with or without total body irradiation plus HSCT, the following are recommended.
  • Palifermin 60 mcg/kg per day for three days prior to transplant and three days post-transplant
  • Cryotherapy in high-dose melphalan
  • Low-level laser therapy (LLLT) before HSCT

The primary author was the principal investigator on the National Institutes of Health (NIH) R13 Conference Grant that provided partial support for the symposium “Oral Complications of Emerging Cancer Therapies,” 14-15 April 2009, Bethesda, MD, USA. Production of a Journal of the National Cancer Institute (JNCI) Monograph for conference publications was supported by an unrestricted educational grant form Biovirum, which owned palifermin at the time of the publication. Peterson also is a member of the Scientific Advisory Board and a paid consultant for the GI Co., Inc, which is responsible for the development of recombinant intestinal trefoil factor, for which the phase II study is cited in the references.

The mucositis guidelines reported contain few changes from the previous two versions of the ESMO Clinical Practice Guidelines. With the 2009 MASCC/ISCO Mucositis Study Group in June 2009, it was decided that no new guidelines were warranted based on the current published literature. Progress has been made in the understanding of molecular basis of mucositis. Evidence-based, cancer-specific identification of risk factors and management of mucositis depend on clinical research so that approval of new drugs and devices will be possible.

PHASE OF CARE: Active antitumor treatment

Cryotherapy or low-level laser therapy may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. Keratinocyte growth factor (KGF) may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there was a lack of efficacy and significant toxicity data as well as a lack of long-term follow-up data in pediatric cancers. No other interventions were recommended for oral mucositis prevention in children.

• Cryotherapy: Weak recommendation with moderate to quality evidence
• Low-level laser therapy: Weak recommendation with high-quality evidence
• KGF: Weak recommendation with high-quality evidence

No keywords, inclusion criteria, or exclusion criteria were stated in the article.

Although some information was missing in this study, the decision making process and results of the evidence review were well-described. The inclusion of a description of research gaps, summarized in a table, showed the comprehensiveness of this review.