Pilot Study of Laser Effects on Oral Mucositis in Patients Receiving Chemotherapy

PURPOSEThe purpose of this study was to examine the effectiveness of laser therapy in the prevention and/or healing of chemotherapy-induced oral mucositis lesions. This study also evaluated the ease and feasibility of the laser therapy and the impact of the treatment on improving the patient's quality of life. PATIENTS AND METHODSFifteen patients with an episode of prior chemotherapy-induced grade 3 or 4 mucositis with 5-fluorouracil continuous infusion consented to participate in this study. All patients were provided with standardized mouth care instructions at the initiation of chemotherapy treatments. Enrolled patients received laser therapy treatments 24 hours before the chemotherapy and then recommenced weekly with evenly distributed exposure to the standardized designated areas by one operator during the entire cycle of chemotherapy at the same doses until the mucositis resolved or the chemotherapy cycle was completed. Intraoral perfusion was measured by laser Doppler technology. Patients were assessed for response to laser therapy according to standardized mucositis grading criteria by evaluating development of lesions, extent and duration of lesions, and time to healing. The effect of laser therapy on ability to continue planned chemotherapy, the reduction in dose, delays, and ability to maintain planned dose intensity were assessed. The impact of laser therapy on pain control was evaluated using the visual analogue score. A quality-of-life survey was completed by each patient at the initiation of chemotherapy and then weekly throughout the chemotherapy. RESULTSEleven of 15 patients experienced grade 0 mucositis, three patients experienced grade 1 to 2 mucositis, and one patient experienced grade 3 to 4 mucositis. Fourteen patients completed the laser therapy as planned, and none of the patients withdrew from the laser therapy treatments because of noncompliance. One patient continued to experience grade 4 mucositis that necessitated an interruption in the planned chemotherapy regimen and, consequently, the laser treatment. Patients tolerated the laser therapy very well and did not report any increased discomfort. No significant changes in perfusion were observed as a result of laser therapy. DISCUSSIONIn this pilot study, laser therapy significantly reduced the incidence and the severity of mucositis in chemotherapy patients. The laser therapy does not appear to promote wound healing by affecting the intraoral perfusion, as assessed by Doppler measurements. The mechanisms involved in the mediating of the observed effects remain unknown at this time. Continued research is warranted to determine the optimal laser wavelength and parameters.

laser therapy in the prevention and/or healing of chemotherapy-tients experienced grade 1 to 2 mucositis, and one patient experienced grade 3 to 4 mucositis. Fourteen patients completed the induced oral mucositis lesions. This study also evaluated the ease and feasibility of the laser therapy and the impact of the laser therapy as planned, and none of the patients withdrew from the laser therapy treatments because of noncompliance. One treatment on improving the patient's quality of life. patient continued to experience grade 4 mucositis that necessitated an interruption in the planned chemotherapy regimen and,

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consequently, the laser treatment. Patients tolerated the laser therapy very well and did not repor t any increased discomfor t. Fifteen patients with an episode of prior chemotherapy-induced grade 3 or 4 mucositis with 5-fluorouracil continuous infusion No significant changes in per fusion were observed as a result of laser therapy. consented to participate in this study. All patients were provided with standardized mouth care instructions at the initiation of chemotherapy treatments. Enrolled patients received laser ther-

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apy treatments 24 hours before the chemotherapy and then recommenced weekly with evenly distributed exposure to the In this pilot study, laser therapy significantly reduced the incistandardized designated areas by one operator during the entire dence and the severity of mucositis in chemotherapy patients. cycle of chemotherapy at the same doses until the mucositis The laser therapy does not appear to promote wound healing resolved or the chemotherapy cycle was completed. Intraoral by affecting the intraoral per fusion, as assessed by Doppler perfusion was measured by laser Doppler technology. Patients measurements. The mechanisms involved in the mediating of were assessed for response to laser therapy according to stanthe obser ved effects remain unknown at this time. Continued dardized mucositis grading criteria by evaluating development of research is warranted to determine the optimal laser wavelength lesions, extent and duration of lesions, and time to healing. The and parameters. (Cancer J 2002;8:247-254) effect of laser therapy on ability to continue planned chemotherapy, the reduction in dose, delays, and ability to maintain planned K E Y W O R D S dose intensity were assessed. The impact of laser therapy on Mucositis, low-level laser therapy, 5-fluorouracil continuous pain control was evaluated using the visual analogue score. A infusion quality-of-life sur vey was completed by each patient at the initiation of chemotherapy and then weekly throughout the chemotherapy.
Oralmucositisismanifestedasan ulceration of the oral mucosa, which frequently occurs with chemotherapy, when patients may be transiently immunocompromised. Colonization of these ulcerated lesions by indige-stantial weight loss and nutritional deficits. These Patients complications significantly affect chemotherapy delivery Patients 18 years of age or older receiving 5-fluorouracil and dose intensity and may ultimately influence treatintravenous continuous-infusion chemotherapy given ment response. The development of an active therapeufor malignancy and with a prior episode of mucositis tic intervention that can reduce the morbidity of oral of either grade 3 or 4 per standardized mucositis grading mucositis will improve quality of life, compliance with scale (Table 1) were included in these investigations. treatment, and therapeutic outcome.
Continuous infusion 5-fluorouracil was scheduled to be Low-level laser therapy (LLLT) has been used in huadministered for 4 consecutive weeks, followed by a 2mans since the early 1970s. Initially, it was suggested week rest period. Inclusion criteria were a Karnofsky that this form of energy delivery could enhance wound performance status of 50% or higher and a life expechealing. [1][2][3][4] In studies of fibroblast responses to lasers, tancy of $ 2 months. Patients were at least 2 weeks increased cell division and increased collagen producbeyond surgery or 4 weeks beyond radiotherapy and tion have been reported. 5,6 In gingival tissues, low-level other forms of chemotherapy. Patients had recovered laser application stimulated DNA synthesis of myofifrom the associated toxicities of surgery, chemotherapy, broblasts without accompanying degenerative changes or radiotherapy. Their granulocyte count measured at and was able to transform fibroblasts into myofileast 1500/m L, and their platelet count was $ 100,000/ broblasts, which may also promote wound healing. 7,8 m L on initiation of laser treatment. Exclusion criteria Subsequently, the benefit of low-level energy delivery were concomitant or previous radiotherapy to the head systems as an anti-inflammatory and pain-reducing tool and neck area. (i.e., nasopharynx, oropharynx, or larin both animals and humans was suggested. 9-24 One ynx), previous surgery for head and neck malignancy, mechanism postulated for the pain-relieving effects of receipt of retinoid therapy at the time of enrollment, low-level laser therapy is the modulation of nociception wearing of dentures or dental appliances, pregnancy, and by the modification of nerve conduction via the release absence of a medically accepted form of birth control. of endorphins and enkephalins. [25][26][27][28] The respiratory All pretreatment observations were completed within chain enzymes within the mitochondria have been iden-28 days before laser treatment, when a complete history tified as the primary receptor chromophores for lowand physical examination was performed by studylevel laser light. [29][30][31][32][33][34][35][36][37][38][39] Because enzymes are catalysts with participating physicians and a complete oral examinathe capability of processing large numbers of substrate tion was performed by study-participating dentists. All molecules, they may provide amplification or the initiapatients signed an informed consent before study partion of a biologic response with light stimulation.
ticipation. Several recent publications have reported on LLLT use for the prevention or treatment of chemotherapy-Laser Therapy induced mucositis. [37][38][39][40][41] Results were significantly better than traditional methods, especially after the preventive After an episode of grade 3 or 4 mucositis, enrolled patients were scheduled to receive laser therapy or treat-use of LLLT. These studies were executed using laser light at 632 nm at energy densities of approximately ment during subsequent cycles of chemotherapy with the same chemotherapy dosage regimen. Enrolled pa-0.75-1 J/cm 2 . Although the 630-nm wavelength is within the absorption range of tissue, deeper tissue pen-tients received laser therapy treatments 24 hours before the recommencement of chemotherapy and then weekly etration is achieved with wavelengths of 820-840 nm. The 830-nm beam also provides a very effective output throughout the duration of chemotherapy at the same doses until resolution of mucositis or completion of the power, thus reducing laser treatment duration-an important factor in the treatment of debilitated patients. chemotherapy cycle. Patients wore wavelength-specific dark goggles during the procedure to protect their eyes This study examined the effect of laser light at 830 nm on the prevention and healing of oral mucositis from exposure to the laser beam. Patients received laser therapy once weekly to deliver a total of 50-60 J with lesions and determined the ease of administering such treatment. Additionally, the impact of such therapy on an energy density of approximately 0.7-0.8 J/cm 2 . The laser used was a 70-mW device (Lasermedics Inc., Hous-improving the cancer patient' s quality of life while receiving chemotherapy was evaluated.
ton, TX), with a continuous mode of operation and an attached fiberoptic delivery tip. Power emission at the fiberoptic tip measured 45-50 mW (Coherent Field

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Master Consul laser meter, Coherent Co., Auburn, CA). The laser treatment regimen was provided by one experi-The following investigations were performed after protocol review and approval by the University of California, enced clinician in an effort to standardize the laser irradiation procedure as much as possible. Treatment required Irvine Human Subject Review Board. 15-30 minutes per patient with evenly distributed expo-ability to maintain planned dose intensity were assessed.
A quality-of-life survey was completed by patients at the sure in each of the following areas: upper labial surfaces, lower labial surfaces, internal surface of left cheek, inter-initiation of each chemotherapy cycle and then weekly during the entire treatment period. A Karnofsky score nal surface of right cheek, dorsal and ventral surfaces of left half of tongue, dorsal and ventral surfaces of right was also elicited for each week.
Toxicities to be monitored for the laser device were half of tongue, upper left gingival and mucosal quadrant, upper right gingival and mucosal quadrant, lower right minimal because this device has been classified as a nonrisk device by the United States Food and Drug gingival and mucosal quadrant, lower left gingival and mucosal quadrant, left side of palate, and right side of Administration. Toxicities secondary to the chemotherapy were monitored and managed according to the stan-palate.
dard of medical practice.

Patient Assessment
Laser Doppler F lowmetry Patients were assessed weekly by one prestandardized, experienced clinician. Mucositis was quantified on a Laser Doppler flowmetry (LDF) studies were undertaken scale of 0-4 using the standardized mucositis grading to provide information on vascular events in the affected scale (Table 1). Lesion size (approximate area), location, areas. All patients underwent measurement of vascuand duration as well as time to healing were also docularity via LDF weekly, commencing on day 1 of laser mented. Patients took home seven sheets each week treatment. LDF measurements were carried out using that had a schematic drawing of oral surfaces (Fig. 1). the Perimed PF 3 device (Linkoping, Sweden) at the Each day, the patient drew onto this sheet the size, following sites before laser therapy and at the compleextent, and location of any lesions, having been taught tion of the laser treatment: how to do this at the initial visit. Pain was scored daily on a visual analogue scale (VAS) that had a grading 1. Upper left buccal mucosa: above central incisor, first premolar scale from 0 (no pain) to 100 (worst possible pain). In addition, effect of laser therapy on the ability to continue 2. Lower right buccal mucosa: below central incisor, first premolar planned chemotherapy, reduction in dose delays, and  Abbreviation: SD, standard deviation. a The patient who withdrew from the study due to grade 4 mucositis had the pain score of 70. b One patient withdrew from the study due to grade 3-4 mucositis.
3. Upper right palatal mucosa above central incisor, One patient continued to experience grade 4 mucositis that necessitated an interruption in the planned chemo-first premolar; lower left lingual mucosa below central incisor, first premolar therapy regimen and, consequently, the laser treatment.
Patients tolerated the laser therapy very well and did 4. Tongue: tip and 1, 2, and 3 cm from tip on left and right side of tongue not report any increased discomfort due to the laser therapy. Pain scores at baseline and weekly thereafter 5. Cheeks: 1-cm intervals from commissures 6. Inner surface of upper and lower lip between com-up to week 4 of LLLT were not significantly different except in one patient, who withdrew from the study missures at 1-cm intervals because of grade 4 mucositis. This patient had a VAS The LDF probe was fixed in an intraoral custom-made score of 70 at the time of onset of grade 3-4 mucositis stent to ensure reproducible measurement locations and ( Table 2). to prevent probe contact with the oral tissues.
LDF measurements were taken at a total of 25 locations per patient per visit. The measurements differed Statistic al Analysis markedly from one location to the next and between Statistical evaluation was conducted using the Chipatients. In any one standard location, no significant squared test to compare differences between the primary changes in intra-oral perfusion were observed as a result evaluation criterion of the degree of mucositis caused of LLLT, as demonstrated by the Doppler measurements by the same dosage regimen of chemotherapy before general linear procedures: P < 0.05) in all 15 patients and after the low-level laser therapy. Mucositis score at as shown in Fig. 3. the weekly assessment visits and oral pain assessment (VAS scale scores for each day, averaged over each week)

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were used as the primary assessment criteria. A separate evaluation was performed of LDF measurements, also Oral mucositis remains a very problematic adverse effect using the Chi-squared test.
of radiotherapy and anticancer chemotherapy. Cancer chemotherapy agents, such as alkylating agents, antime-R E S U L T S tabolites, and antimitotic agents, aim to kill rapidly proliferating cells. Alkylating agents affect the DNA in all A total of 15 patients were initiated in the laser therapy.
phases of the cell cycle to prevent cell reproduction. Each patient received a minimum of three and a maxi- The antimetabolites block the biosynthetic pathway in mum of seven laser treatments during this study. Before the S phase by interfering with the biosynthesis of pu-LLLT, all 15 patients had experienced grade 3 or 4 rines and pyrimidines. The antimitotic agents disrupt mucositis during chemotherapy. With LLLT, under the the microtubules during metaphase in the M phase. same chemotherapy regimen, 11 patients experienced However, chemotherapeutic agents are nonspecific. grade 0 mucositis, three patients experienced grade 1-2 While destroying malignant cells, they also adversely mucositis, and one patient experienced grade 3-4 mucoaffect normal host cells with high mitotic indices. The sitis (Fig. 2). Fourteen patients completed the laser thernormal cells with a very high rate of proliferation that are apy as planned, and none of the patients withdrew from adversely affected by chemotherapy particularly include the laser therapy treatments because of noncompliance. those in oral and gastrointestinal mucosa and the hematopoietic system. Some degree of oral mucositis occurs in approximately 40% of patients who receive anticancer which results in the production of ulcerative lesions and typically begins about 4 to 5 days after anticancer chemotherapy. 42 The percentage increases drastically in patients who are treated with localized radiotherapy treatment administration.
The ulcerative/microbiological phase is characterized to the head and neck regions, especially when concurrent chemotherapy is administered and patients may by the breakdown of mucosal barriers. This phase tends to be most symptomatic and places patients at the high-be transiently immunocompromised. Colonization of ulcerated mucositis lesions by indigenous bacteria may est risk of secondary infection.
The final, healing phase occurs when the renewal of lead to systemic infection and septicemia in patients who are rendered neutropenic by chemotherapy. cell proliferation and differentiation allows for return to normal of peripheral blood counts and control of oral Presently, few direct measures exist to prevent development or promote healing of mucositis lesions. Care gen-microbial flora.
The search for the prevention and treatment of oral erally consists of vigorous mouth cleansing, but the oral cavity cannot be fully decontaminated. Thus, care is mucositis remains a challenge for health care providers.
Current treatment options are primarily supportive and aimed at symptom control until immune function recovers. Mucositis is painful, and many patients have signifi-are less than optimal. Recent approaches to the prevention and treatment of mucositis induced by anticancer cant pain that requires parenteral narcotic analgesia. Mucositis can also limit adequate nutritional intake. treatments can be primarily categorized according to the specific phase of the biologic process being targeted. Patients generally experience substantial weight loss and nutritional deficits. Mucositis also diminishes patients' Cryotherapy causing vasoconstriction and temporarily reducing the oral mucosal blood flow has been used quality of life, which may result in serious clinical complications and can decrease the willingness of patients to target the initial vascular phase. This therapy has been shown to effectively decrease 5-fluorouracil-in-to continue treatment. More severe mucositis with extensive ulceration may require costly hospitalizations duced and melphalan-induced mucositis but only when the drugs are given on short infusions. 42,44 Cytoprotec-with parenteral nutritional support and narcotics. These complications significantly affect radiotherapy and che-tion using prostaglandin E 2 , vitamin E, and b -carotene (a vitamin A precursor) had been investigated, but their motherapy delivery and dose intensity and may ultimately influence treatment response. The development roles remain to be determined. [45][46][47] Inhibition of factors involved in the cycling of epithelial cells such as trans-of an active therapeutic intervention, which can reduce the morbidity of oral mucositis, may improve quality forming growth factor b 3 is being studied. However, the potential of this agent in protecting the proliferating of life, compliance with treatment, and therapeutic outcome.
tumor cells against the action of chemotherapy must be ruled out before it is used in the supportive treatment The complete pathophysiology of mucositis continues to be ill defined. On the basis of animal and clinical of mucositis. 48 Several growth factors have been tested to attempt to data, a publication by Pico et al 43 attempted to summarize the mechanisms by which mucositis develops and acceleratethe restoration of normal epithelium. Granulocyte colony stimulating factor and granulocyte colony heals, but the outcome remains speculative. In this article, mucositis was described as a four-phase biologic stimulating factor promote the proliferationand differentiation of neutrophils and monocyte/macrophage, and process that involves an inflammatory/vascular phase, an epithelial phase, an ulcerative/microbiological phase, several studies have demonstrated a decrease in the incidence and the severity of mucositis with these agents. 49-and a healing phase. Each of these phases is independent and is a result of a series of actions mediated by cytokines 52 A direct effect of granulocyte macrophage colony stimulating factor on the oral mucosa has been demon-and other growth factors, the direct effect of the anticancer treatments on the epithelium, the oral microbials, strated. 53 The cost of this treatment and the optimal time of administration continue to be a challenge for and the status of the immunocompromised host response.
investigators. Keratinocyte growth factor, an epithelial growth factor produced by stroma cells to induce prolif-The inflammatory/vascular phase is relatively acute and is caused by the anticancer treatment' s causing the eration and differentiation of epithelial cells, is also being evaluated. 54 release of cytokines (e.g., interleukin-1) from the epithelium and the connective tissue. Cytokines such as tumor Oral glutamine is currently considered to be a promising advancement in the management of oral mucositis. necrosis factor and interleukin-1 can cause an inflammatory response that may result in increased subepithelial Glutamine is a nonessential amino acid and is a wellknown mucosal protector of the bowel. Two studies vascularity.
The epithelial phase is primarily caused by drugs investigating the role of oral glutamine in reducing chemotherapy-induced oral mucositis revealed positive re-that target the DNA synthesis (S phase of the cell cycle), which are more mucotoxic than other drugs. This phase sults. 55,56 A recent trial showed that gargling with glutamine suspension also reduced both the duration is documented by the reduction of epithelial renewal, and the severity of radiation-induced oral mucositis R E F E R E N C E S which supports the concept of a local rather than a 1. An increase in the number of S-phase cells, con- It is possible to conclude that the LLLT can enhance 47-50. the metabolic process in the cell and activate the prolifer- tively low (10-1000 J/m 2 ) and the irradiation times needed are relatively short (10-100 seconds).
In conclusion, these studies demonstrated the ability 19. Shiroto C, Ono K, Oshiro T. Laser stimulation therapy using a of low-level laser therapy to reduce the incidence and parameters. Cellular and molecular investigations are also indicated to define the mechanisms of laser effects. 22. Shiroto C, Ono K, Ohshiro T. Retrospective study of diode laser