Low-level laser therapy in the prevention and treatment of chemotherapy-induced oral mucositis in young patients

Photomedicine and Laser SurgeryVolume 26, Number 4, 2008 Mary Ann Liebert, Inc.
Pp. 393–400DOI: 10.1089/pho.2007.2144 Low-Level Laser Therapy in the Prevention and Treatment of Chemotherapy-Induced Oral Mucositis in Young Patients Meire Maman Fracher Abramoff, D.D.S.,6 Nilza Nelly Fontana Lopes, D.D.S., M.S.,1 Luciana Almeida Lopes, D.D.S., M.S., Ph.D.,2 Luciano Lauria Dib, D.D.S., M.S., Ph.D.,3 Arnaldo Guilherme, M.D., Ph.D.,4 Eliana Monteiro Caran, M.D., Ph.D.,1 Adriana Delboni Barreto, D.D.S.,6 Maria Lucia Martinho Lee, M.D.,5 and Antônio Sérgio Petrilli, M.D., Ph.D.1 Abstract
Objective: A pilot clinical study was conducted to evaluate the efficacy and feasibility of low-level laser ther-
apy (LLLT) in the prevention and treatment of chemotherapy (CT)-induced oral mucositis (OM) in young pa-
tients.
Background Data: Besides compromising the patient’s nutrition and well-being, oral mucositis represents a
portal of entry into the body for microorganisms present in the mouth, which may lead to sepsis if there is
hematological involvement. Oncologic treatment tolerance decreases and systemic complications may arise that
interfere with the success of cancer treatment. LLLT appears to be an interesting alternative to other approaches
to treating OM, due to its trophic, anti-inflammatory, and analgesic properties.
Materials and Methods: Patients undergoing chemotherapy (22 cycles) without mucositis were randomized
into a group receiving prophylactic laser-irradiation (group 1), and a group receiving placebo light treatment
(group 2). Patients who had already presented with mucositis were placed in a group receiving irradiation for
therapeutic purposes (group 3, with 10 cycles of CT). Serum granulocyte levels were taken and compared to
the progression of mucositis.
Results: In group 1, most patients (73%) presented with mucositis of grade 0 (p ϭ 0.03 when compared with
the placebo group), and 18% presented with grade 1. In group 2, 27% had no OM and did not require therapy.
In group 3, the patients had marked pain relief (as assessed by a visual analogue scale), and a decrease in the
severity of OM, even when they had severe granulocytopenia.
Conclusion: The ease of use of LLLT, high patient acceptance, and the positive results achieved, make this ther-
apy feasible for the prevention and treatment of OM in young patients.
Introduction
The estimated incidence of oral complications4 varies with the type of therapy patients undergo, but occurs in approx- PATIENTS WHO UNDERGO CHEMOTHERAPY (CT) and radio- imately 40% of patients receiving chemotherapy, 80% those
therapy (RT) for the treatment of malignant neoplasia of- receiving bone marrow transplants, and 100% of patients re- ten present with oral mucositis (OM) as a side effect. This ceiving radiotherapy of the head and neck, if the oral cavity stomatotoxicity strongly impacts the quality of life of these is in the irradiated field. Younger patients have a higher in- individuals, with higher morbidity and mortality rates and cidence of oral complications5 than older patients receiving length of hospital stay, that lead to higher costs of treatment.1 Thus from the patient’s point of view, OM is the most de- CT’s cytotoxic action on the epithelial basal cell layer leads bilitating complication accompanying a bone marrow trans- to a decrease in the renewal rate of these cells, with atrophy and ulceration of the tissues. These drugs simultaneously at- 1Pediatric Oncology, Institute IOP GRAACC/UNIFESP, Federal University of São Paulo, 2Research and Education Center for Photo Therapy in Health Sciences (NUPEN), 3Stomatology, Paulista University (UNIP), 4Otorhinolaryngology and Head and Neck Surgery,UNIFESP, Federal University of São Paulo, 5Pediatric Institute (IOP/GRAACC/UNIFESP), Federal University of São Paulo, and 6Privatepractice, São Paulo, Brazil.
ABRAMOFF ET AL.
tack the bone marrow, inducing granulocytopenia and posed to demonstrate these beneficial effects for the pre- thrombocytopenia, and predisposing the patient to infec- vention and treatment of OM in oncologic patients,43–54 but tions and bleeding.6 The ulcerated oral epithelium allows en- comparisons are difficult due to the lack of standardization try into the body of the oral microbiota, and may cause lo- cal and systemic infections. With the oral pain they suffer, OM is a result of various etiological agents and has char- patients tend to become dehydrated and malnourished.
acteristics that change as it progresses. LLLT acts in a bene- The cellular and molecular changes seen as mucositis pro- ficial and non-invasive way, producing no collateral effects.
gresses7 occur soon after the administration of RT or CT, and Based on the accumulated evidence, the Multinational As- lead to DNA strand breakage and the liberation of reactive sociation of Supportive Care in Cancer and the International oxygen species (ROS). The ROS activate transcription factors Society for Oral Oncology (MASCC/ISOO)55,56 suggest the use such as P-53 and nuclear factor-␬B,8 leading to cell death.
of LLLT for OM prevention in hematopoietic stem cell trans- These transcription factors also induce liberation of cyto- plant patients. Nevertheless, no guidelines have been estab- kines, such as tumor necrosis factor-␣, interleukin-11␤, and lished and further studies should be well designed. The aim interleukin-6, which are responsible for alterations in the of this clinical pilot study is to evaluate the efficacy and feasi- connective tissue9 and endothelium,10 with consequent dam- bility of LLLT in the prevention and treatment of OM in young age to the basal layer of the epithelium. The healing of non- patients who are undergoing high-dose chemotherapy.
infected mucositis occurs in a physiological way, and is as-sociated with decreases in drug toxicity and re-establishment Materials and Methods
of the granulocyte count,7,11 which favor the healing process.
These biological events are influenced by various factors, such as drug toxicity, dose, the interval between cycles, as- This prospective, randomized, placebo-controlled study sociated radiotherapy, the general health of the patient, sus- was approved by the Ethics Committee and developed for ceptibility to the CT agents, and patient dental condition and outpatients of the Pediatric Oncology Institute (GRAACC) of São Paulo Federal University between February and Au- There is a wide range of procedures and products to alle- gust 2003. All patients or their parents or guardians signed viate the effects of oral mucositis, such as antimicrobial rinses, mucosa protectants, cryotherapy, topical analgesics, A total of 13 patients were included, with a total of 32 CT and more recently the use of keratinocyte growth factor-112 cycles, of which 21 cycles were for osteosarcoma treatment, and phototherapy such as low-level laser therapy (LLLT).
and 11 cycles were for high-risk acute lymphoid leukemia The mechanism behind the laser’s interactions with bio- (ALL) treatment. There were 5 males and 8 females and their logical tissues is only partly understood, but it is described mean age was 14.6 y (range 7–23 y).
as a photobiological phenomenon in which primary pho- The CT regimens of the osteosarcoma patients are sum- toacceptors (chromophores) such as cytochrome c oxidase, marized in Table 1. The patients who underwent ALL treat- flavins, and porphyrins, absorb certain wavelengths, caus- ment received CT in accordance with the criteria of the ing a cascade effect in the respiratory chain, which results in Brazilian Group for the Treatment of Leukemia in Childhood the production of energy to fuel cell metabolic processes.13,14 LLLT’s photostimulation of biological tissues depends on Patients with unstable clinical condition, severe oral in- the use of the proper parameters, and this is still under in- fections, and those with head and neck malignancies were vestigation, but since the 1960s15,16 there has been strong ev- idence indicating the potential of LLLT to hasten healing.
Laser therapy enhances microcirculation,17–20 improves lym- phatic drainage,21–23 promotes pain relief,24–29 and increasesproliferation and mobility of epithelial cells.16,30–32 There are Standardized methods of oral hygiene were established also significant increases in fibroblast production and activ- with the use of soft toothbrushes and mouth rinsing with bi- ity,33–38 which accelerate collagen synthesis.39–42 carbonate solution four times a day. Adequate oral intake Our improved understanding of the pathophysiology of was achieved before CT to avoid trauma and to reduce the OM has made possible the introduction of new approaches to treat the manifestations of stomatotoxicity. Recently pub- Patients without OM when they begun CT were random- lished studies have demonstrated the wide range of benefits ized into group 1 (prophylactic laser irradiation) or group 2 of LLLT for biological tissues. Several trials have been pro- TABLE 1. CHEMOTHERAPY PROTOCOL FOR THE PATIENTS WITH OSTEOSARCOMA LLLT IN THE MANAGEMENT OF CHEMOTHERAPY-INDUCED ORAL MUCOSITIS
High-risk
and/or peripheral blasts in D14and/or BM M2/M3 in D28 Remission
Remission
induction
induction
M1 / M2 / M3
Intensification
Late consolidation
Maintenance
The chemotherapy protocols of the patients with high-risk ALL. BM, bone marrow; BMT, bone marrow trans- plantation; MTX, methotrexate; DEXA, dexamethasone; VCR, vincristine; L-ASP, L-asparaginase; DAUNO, daunorubicin;6-TG, 6-thioguanine; CYCLO, cyclophosphamide; 6-MP, 6-mercaptopurine; ARA-C, cytarabine; VP-16, etoposide; IFO, ifos-famide; MADIT, methotrexate ϩ ARA-C ϩ dexamethasone intrathecal.
Patients presenting with OM at their first examination tis, between the sixth and ninth days after beginning CT. The were placed in group 3 (therapeutic laser irradiation).
patients in both groups were blinded as to whether they re- The beginning of each CT cycle was considered a new case and the patients were subjected to new randomization.
The prophylactic laser group and the placebo laser group The first laser irradiation session was done as soon as mu- The first irradiation was performed within 24 hours of be- cositis was diagnosed, and the two following sessions were ginning CT, and the next two irradiations were performed every other day. The third one corresponded with the be- The clinical evaluations were conducted prior to irradia- ginning of the period of highest risk of developing mucosi- tion. After a total of three laser therapy sessions, patients ABRAMOFF ET AL.
TABLE 2. CHANGES IN MUCOSITIS GRADE IN PATIENTS Pain scored from 1–4 was considered mild, that scored from 4.1–7 was moderate, and scores Ն7 were considered intense.
In the presence of infections caused by fungi, bacteria, or viruses, a therapeutic regimen was established, and the eval- uation of laser effectiveness was restricted to signs and symptoms of OM lesions, without consideration as to whether the laser therapy could cure the infection.
Granulocyte levels were evaluated because they behave similarly to the epithelial cells of the oral mucosa when ex- posed to CT agents. The granulocyte levels were classified one of three ways: Ն2000/mm3, from 1000–2000/mm3, and Ͻ1000/mm3. Filgrastim use was also considered because itraises serum granulocyte levels.
who did not present with mucositis were excluded from the protocol. If mucositis persisted, more laser sessions werescheduled.
The mucositis grades and granulocyte levels were com- pared at the first and third evaluation. Then the mucositis grades of the prophylactic laser group were compared withthose of the placebo laser group.
An AsGaAl diode laser was used (THERA LASER; DMC The results were analyzed using the comparison test for Equipments Ltda. São Carlos, Brazil) operating at 685 nm, two proportions, which is a non- parametric qualitative test.
35 mW output power, continuous wave, and a 600-␮m spot.
The value considered statistically significant was p Ͻ 0.05.
The energy delivered was 2 J per point of application, andthe fluence was approximately 72 J/cm2. The time spent at each point was 54 sec. Laser energy was application punc-tually, perpendicular to the tissue. The tip of the laser was disinfected with 70% alcohol solution and wrapped with a There were seven patients in this group, with a total of 11 plastic film. Patients and operators wore glasses for eye pro- CT cycles. All patients were undergoing osteosarcoma treat- The following areas were irradiated: the left and right ju- In the third evaluation, among the 8 patients without mu- gal mucosa (two points on each side), the superior and in- cositis (Table 2), there were 5 cases with granulocyte levels ferior internal lip mucosa (one point in each quadrant), the Ͻ2000/mm3 (Table 3). It must be emphasized that two pa- floor of the mouth (one point on each side), the lateral edge tients with granulocyte levels Ͼ2000/mm3 had taken fil- of the tongue (two points on each side), the tip of the tongue (one point), the smooth palate (one point on each side), and In the second evaluation, candidiasis was diagnosed in the patient who presented with grade II mucositis. Once the in-fection treatment regimen was established, laser application was performed and this patient reported pain reduction from Patients were clinically evaluated with regard to OM severity, painful symptomatology, esophagitis, and they In the second evaluation, esophagitis was observed in just were asked if they used filgrastim (Granulokine®). The one patient. This patient reported intense pain in the phar- changes in granulocyte levels were evaluated through hema- ynx (grade 9), but for the oral-cavity mucositis the grade was 0, and granulocyte levels were Ͻ1000/mm3. In the third eval- Oral mucosal toxicity and esophagitis were graded ac- uation, three patients presented with esophagitis, but did not cording to the National Cancer Institute’s Common Toxicity present with mucositis in the oral cavity.
Criteria, version 2.0.57 Pain was evaluated before and after All patients progressed toward the resolution of OM with laser application via a visual analog scale scored from 0–10.58 TABLE 3. CHANGES IN GRANULOCYTE LEVELS IN PATIENTS LLLT IN THE MANAGEMENT OF CHEMOTHERAPY-INDUCED ORAL MUCOSITIS
TABLE 4. CHANGES IN MUCOSITIS GRADE IN PATIENTS cles were for ALL. These patients had already shown some degree of mucositis at the first evaluation. This group hadCT beginning on the date of the first examination, and con- tinued it for 1–7 d, with an average of 3 d.
At the first evaluation of the protocol, seven episodes of pain were noted, two of them (29%) mild pain, and five (71%) moderate pain. At the second evaluation, after one laser ses-sion, five reported (71%) episodes of mild pain, and two (29%) episodes of moderate pain. At the third evaluation, of the 10 CT cycles evaluated, only three (30%) cases of mild pain were noted; however, these patients were able to speak and eat in spite of the pain. At the third evaluation only oneoccurrence of moderate pain was noted, and after anotherlaser session it became mild.
At the third evaluation, most patients regardless of their low granulocyte levels (80% of patients), did not have severemucositis (Table 6), and they could eat and continue their Seven patients were evaluated, having a total of 11 CT cy- cles. Among them, 5 cycles were for osteosarcoma treatment, Also at the third evaluation, among the six patients with and 6 cycles were for ALL treatment.
granulocyte levels Ͻ1000/mm3 (Table 7), two of them pre- Some patients (3) presented with grade I mucositis at the sented with grade 0 mucositis, one patient had OM grade I, first examination, but they were randomized into this group and three patients had OM grade II. The patients with grade because they had mild edema in the jugal mucosa. All these II OM had grade III OM at the previous evaluations, and patients maintained grade I mucositis during all three eval- they improved after LLLT in spite of granulocytopenia. OM healing occurred in all of them, with no need for further In this group mucositis episodes were frequent (Table 4), but they were not as severe, because when grade II mucosi-tis was diagnosed, therapeutic measures had already been Discussion
established. Also, these patients were under supervision,which may have promoted better oral hygiene, which is LLLT was well tolerated, even when patients presented known to decrease the severity of OM.
with severe lesions, which makes this therapy tolerable to The levels of granulocytes in the placebo group did not children. There were no patients who discontinued LLLT be- cause they found it to be unacceptable. With the improve- At the first evaluation, no patients reported pain, while at ment in signs and symptoms, some patients did not attend the third evaluation three patients mentioned pain in the oral the following sessions, which made follow-up of these pa- cavity. Two patients had viral infections at the third evalu- ation, and therapeutic intervention was necessary in three Several patients repeated the CT cycles with similar drugs and dosages, and were randomized once again within theLLLT protocol. This procedure allowed the comparison of Placebo versus prophylactic laser group different approaches to treating OM in the same patient, orin those with similar CT protocols.
At the third evaluation, 73% of the patients in the pro- For instance, two patients with the same disease and sim- phylactic laser group did not have mucositis, and in the ilar CT regimens (high-dose methotrexate) were included in placebo group 27% had no mucositis, a difference that the prophylactic laser group, and later, because at the first reached statistical significance (p ϭ 0.03).
examination they had already presented with signs of OM,they were included in the therapeutic laser group. When they were prophylactically irradiated they had mucositis grade 0 Six patients (10 CT cycles in all) were followed-up. Five or I at the three evaluations. On the other hand, when the cycles were given for osteosarcoma treatment, and five cy- therapeutic laser protocol was used, they developed mu- TABLE 5. CHANGES IN GRANULOCYTE COUNT IN PATIENTS ABRAMOFF ET AL.
TABLE 6. CHANGES IN MUCOSITIS GRADE IN PATIENTS tablishment of conditions that favor healing occurs. We ob- served a decrease in the intensity of OM, even in those withsevere granulocytopenia.
The difficulty of demonstrating the laser’s efficacy in on- cologic patients with OM results from the variety of disease types and chemotherapy and radiotherapy protocols. There is also a lack of a consistent classification system to evaluatethe severity of OM, and the possibility of spontaneous heal- ing in many cases without complications. As CT agents have different toxicity levels, the short interval between CT cycles makes it difficult to determine which drugs may intensify Also, it was difficult to determine the appropriate laser pa- rameters to use in pediatric patients. The energy levels usedhere were based on several small pilot studies performed by cositis grade III at the second evaluation, and mucositis our group. From an initial energy level of approximately 1 J, we evaluated clinical responses with levels up to 3 J. We It was also possible to compare three CT cycles with high- found 2 J to be a good compromise between the results ob- dose methotrexate in a patient. We noted remarkable results: tained and the time spent on laser application.
in the first two cycles with prophylactic laser irradiations, The reduction in OM-induced pain was the most remark- the patient presented mucositis grades 0 and I. In the third able effect reported by our patients, a fact in agreement with cycle, this patient was randomized to the placebo group data found in the literature.43–45,47,51,53,54 This prompt alle-and mucositis grade III was diagnosed, and required addi- viation allowed patients to improve their nourishment, which improved their overall state of health.
Methotrexate (MTX) and cytarabine (ARA-C) are an- The ease of use of LLLT, the ability to treat OM in a few timetabolite cell-cycle-phase specific drugs with significant irradiation sessions, the low cost of the equipment, the high cytotoxic potential for the oral and gastric mucosa. In the patient satisfaction with the protocol, and the successful re- protocol for ALL treatment these agents were administrated sults obtained in this study, make this therapy feasible for simultaneously or over a short time interval. For osteosar- the prevention and treatment of OM in pediatric patients.
coma treatment, the recommended dose of MTX was 12g/m2, as an alternative therapy regimen for patients with re- Conclusion
In spite of our small patient sample, it is worth noting that The use of LLLT for prophylactic purposes showed the most did not develop OM when prophylactically irradiated, most satisfactory outcomes, a fact in accordance with data and there was quick recovery and pain relief for those in the found in the literature.43–46,48–50,52–54 For therapeutic appli- therapeutic laser group, even in those with significant gran- cations, the patients noted pain relief, and there were no re- ulocytopenia, thus enabling them to better tolerate their che- ports of OM worsening after LLLT, even when the granulo- motherapy regimens. This demonstrates that LLLT has both a preventive and a therapeutic role in those prone to develop Some authors also demonstrated that light-emitting OM. Further clinical studies are needed with greater num- diodes are helpful in treating OM.59,60 Their effects similar bers of patients to optimize the laser parameters, to test to those of LLLT are explained by the fact the coherence of LLLT’s effectiveness with various CT regimens, and to fur- laser light is lost in the top layers of biological tissues, and ther explore this treatment option for OM, which could thus the photo-stimulatory effects are more related to the light’s parameters than to the light source employed.61 In the present study, the comparison of the evolution of Acknowledgments
mucositis with the granulocyte count allowed differentiationof beneficial laser effects from those of the physiologic evo- We want to thank all of the patients and their families.
lution of OM. Also, when drug toxicity is reduced, the re-es- Thanks also to Armando Reis Tavares, Jimmy Adans, Maria TABLE 7. CHANGES IN GRANULOCYTE LEVELS IN PATIENTS LLLT IN THE MANAGEMENT OF CHEMOTHERAPY-INDUCED ORAL MUCOSITIS
Cristina Iglesias, and Ricardo B. Iannuzzi for assistance in duced spasm in atherosclerotic Yucatan micro-suine. Circu- manuscript preparation. We also thank Mr. Renaldo Mansini, Jr. of DMC Equipmentos Ltda., São Carlos, Brazil, 19. Maegawa, Y., Itoh, T., Hosokawa, T. et al. (2000). Effects of for the aid with the laser equipment.
near-infrared low-level laser irradiation on microcirculation.
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