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Phase III trial of low-level laser therapy to prevent oral mucositis in head and neck cancer patients treated with concurrent chemoradiation
Radiotherapy and Oncology, 2, 109, pages 297 - 302
Oral mucositis (OM) is a complication of chemoradiotherapy treatment of head and neck squamous cell carcinoma (HNSCC) patients with no effective therapy. This study was designed to assess the efficacy of preventive low-level laser therapy (LLLT) in reducing the incidence of grade 3–4 OM.
Material and methods
From June 2007 to December 2010, 94 HNSCC patients entered a prospective, randomized, double-blind, placebo-controlled phase III trial. Chemoradiotherapy consisted of conventional radiotherapy plus concurrent cisplatin every 3 weeks. A diode InGaAlP (660 nm–100 mW–1 J–4 J/cm2) was used. OM evaluation was performed by WHO and OMAS scales and quality of life by EORTC questionnaires (QLQ).
A six-fold decrease in the incidence of grades 3–4 OM was detected in the LLLT group compared to the placebo; (6.4% versus 40.5%). LLLT impacted the incidence of grades 3–4 OM to a relative risk ratio of 0.158 (CI 95% 0.050–0.498). After treatment QLQ-C30 showed, differences favoring LLLT in physical, emotional functioning, fatigue, and pain; while the QLQ-H&N35 showed improvements in LLLT arm for pain, swallowing, and trouble with social eating.
Preventive LLLT in HNSCC patients receiving chemoradiotherapy is an effective tool for reducing the incidence of grade 3–4 OM. Efficacy data were corroborated by improvements seen in quality of life.
Keywords: Low-level laser therapy, Oral mucositis, Head and neck cancer, Radiotherapy, Chemotherapy, Quality of life.
Oral mucositis (OM) is a limiting factor in the treatment of patients suffering from head and neck squamous cell carcinoma (HNSCC) who undergo chemoradiotherapy. Its pathobiology is associated with injuries that occur in the epithelial and connective tissues as a response to a complex cascade of biological events , , and . Between 80% and 100% of all chemoradiotherapy-treated patients present OM , , , , , and  in different grades, starting from radiation doses between 15 and 20 Gy , , and . Severe OM (grades 3–4) is associated with increased morbidity (pain, dysphagia, weight loss, and reduced treatment compliance), poor quality of life, and higher hospital costs due to the need for medication, gastrostomy, and frequent appointments with the health-care team , , , , , and . Besides severe OM may lead to treatment interruption, which may jeopardize the local control of the disease and patient survival  . Therefore strategies to prevent severe OM should be eagerly pursued.
Prospective placebo-controlled clinical trials, have shown that low-level laser therapy (LLLT) can be effective in the prevention of OM in patients undergoing hematopoietic stem cell transplantation , , , , and . However, in the setting of HNSCC patients treated with chemoradiotherapy a definitive trial is needed. Most of the initial trials included patients who underwent radiotherapy only , , and  while in the only four chemoradiotherapy-based studies , , , and , a high incidence of OM was still observed.
Here we assessed the efficacy of LLLT in reducing the incidence of OM in HNSCC patients undergoing concurrent chemoradiotherapy and its impact on the patients’ quality of life.
From June 2007 to December 2010, a randomized, double-blind, prospective, placebo-controlled trial that included 94 HNSCC patients was carried out at the Brazilian National Cancer Institute in Rio de Janeiro. Patients were randomized into two groups of 47 patients each, which received either preventive LLLT or placebo.
To be included in the study patients had to be ⩾18 years, have a histological diagnosis of squamous cell carcinoma (nasopharynx, oropharynx and hypopharynx), be ineligible candidates for surgery, be eligible to a combined treatment with radiotherapy and concurrent platinum-based chemotherapy, have a ECOG performance status (PS)  , of 0 or 1 and have the oral mucosa intact. Patients who were receiving medication for the treatment and prevention of mucositis, and those incapable of complying with the treatment procedure or performing the oral hygiene protocol were not included.
Patients were evaluated by a dentist before starting the radiotherapy and any required dental treatment or the removal of teeth with uncertain prognosis, including teeth with active periodontal disease, teeth requiring endodontic treatment and teeth with cavities or extensive coronal destruction, was performed , , , and . The study was approved by the institutional ethics committee under number MS-17/2007, in accordance with the guidelines of Good Clinical Practice and the Brazilian law, and all patients signed an informed consent form.
Patients were randomized in a non-stratified manner to study treatment and underwent the same protocol of chemoradiotherapy. The chemotherapy protocol was cisplatin (100 mg/m2) on D1, D22 and D43. With the patients supine and immobilized by a thermoplastic mask, megavoltage RT was delivered by two or three-dimensional techniques. A total dose of 70.2 Gy (prescribed at midline) was delivered daily in 39 fractions on a 5 day-per-week schedule with a telecobalt unit and linear accelerator. Radiotherapy began on D1 and the posterior spinal cord was excluded from the treatment volume after 45 Gy. The primary tumor and the upper cervical lymph node regions were treated with two lateral fields. After spinal cord exclusion, additional electron fields (9–15 MeV) at 85–95% curves were used to boost the posterior lymph node chain. The lower neck was treated with an anterior field, to a given dose of 50.4 Gy in 28 fractions. Standard field limits were used for the primary site and the lymph node regions. Portals were verified at D1 and weekly to check positioning. All the recommendations listed at the ICRU report 29 for 2D planning  and at the ICRU reports 50 and 62 for 3D planning  and  were followed and achieved in 92.5% of the patients. In only 7 patients a gradient superior of −5% to +7% (13–20%) was documented. As a preventive measure for candida infection all patients were prescribed oral fluconazole (50 mg/day), starting at D6 until the end of radiotherapy , , and . In patients with a weight loss of 10% or more before or during treatment, with grade 4 OM or with pain on a visual analog scale (VAS) ⩾6 (after opiod analgesic), a percutaneous gastrostomy or nasogastric feeding tube was done. All patients underwent oral hygiene with an extra-soft toothbrush and peroxidase-based system toothpaste after every meal and alcohol-free 0.12% chlorhexidine mouthwash  twice a day, from the first until the the last fraction of radiotherapy ( Fig. 1 ).
Laser therapy protocol
An InGaAlP (indium phosphide, gallium and aluminum) diode laser (DMC, São Carlos, São Paulo, Brazil), with 100 mW, 1 J, 4 J/cm2, a spot size of 0.24 cm2, emitting continuous light at 660 nm, was used for laser therapy. The same energy and energy density was used for all the patients. The preventive LLLT was applied daily, for 5 consecutive days (Monday to Friday), every week, immediately before every single fraction of RT by a dentist and the tip touched the mucosa of the lips, right and left buccal mucosa, left and right lateral tongue border, buccal floor, and ventral tongue, totaling nine points per region. The application time per point was 10 s and the total application time was 12 min. Exactly the same protocol was applied to the placebo group except that the laser tip produced no light. All patients used blinded glasses and were unable to see the dental procedure. For ethical purposes, patients in the placebo group who had grade 3–4 OM or presented a 6 cm of ulcerated area in the oral cavity, were discontinued from the trial and received LLLT (660 nm, 100 mW, 2 J, 8 J/cm2, per point) with therapeutic purposes.
The dentists who applied the LLLT (HSA and MPR) knew which patients were allocated to each study group, but the nurses (TGPS and EC) who evaluated the oral cavity of the patients daily were blinded.
With the purpose of minimizing interobserver variation and familiarizing the team with the measurement scales for mucositis, all professionals involved were submitted to a specific training and testing before the initiation of the trial. A CD-ROM containing the research protocol as well as photographic examples of normal and damaged oral mucosa (mucositis) was given to all professionals involved in the application of LLLT and in the evaluation of patients. Daily evaluation of the mucosa of the lips, right and left buccal mucosa, left and right lateral tongue border, buccal floor, ventral tongue and oropharynx was performed according to the World Health Organization (WHO) mucositis scale  and the OM Assessment Scale (OMAS)  . Every day adverse events were recorded following the Common Toxicity Criteria of the NCI version 3.0  . A modified visual analog scale (VAS) for pain assessment was used  . The opioid use was assessed in accordance with WHO for oral or oropharyngeal pain (in morphine equivalents)  . Body weight (Body Mass Index) was measured weekly from the first day of treatment. All information related to complications occurring during the treatment (such as treatment interruption, treatment delay, patient weight loss, hospitalizations, requirement for nasogastric tube or gastrostomy, and use of opioid analgesic) were recorded. Quality of life (QoL) was assessed on the 1st, 20th and 39th RT fraction by EORTC questionnaires  QLQ-C30 (overall quality of life; version 3.0) and QLQ-H & N35 (specific quality of life for head and neck patients). Patients who missed consultation (⩾3, corresponding to 7.7% of applications) for the application of either LLLT or placebo were considered to be noncompliant and were discontinued from the trial. OM was not evaluated after it. Data related to the primary endpoint were handled in a per protocol treatment analysis. Yet, a strict follow up of every single patient was carried out for disease progression and overall survival data.
The primary end point of the study was the incidence of grade 3–4 OM according to the WHO scale. Assuming an α = 0.05 and a β = 0.20, with the estimates of proportion being 0.40  for placebo (P0) and 0.15  for LLLT (P1) a total of 94 patients were evaluated. The chi-square test (χ2) and the Fisher’s exact test were applied to evaluate the incidence of mucositis according to the WHO scale, VAS for pain scores, interruption of treatment, hospitalization, tumor response, patient exclusion, the need for nasogastric tube or gastrostomy and baseline characteristics of the patients. Logistic regression modeling was undertaken to determine the impact of some variables on the incidence of grade 3–4 OM. The oral mucositis-free interval was calculated from the date of the first radiotherapy to the date of first grade 3–4 OM by the Kaplan–Meier method  and the curves were compared by log-rank tests. The Student’s T test was used to analyze the data obtained from OMAS and QLQ questionnaires. The concordance index between the evaluators was measured by the Kappa test. Analyses were performed using SPSS Statistical Software 18.0. One-sided test error was the basis for the sample size determination and all the reported P-values were derived from two-sided statistical tests. P-values less than or equal to 0.05 were considered statistically significant.
A total of 106 consecutive patients were screened to have 94 patients randomized. Twelve patients did not meet the inclusion criteria. Patients were planned with two-dimensional (LLLT group (LG) = 82.9%; Placebo group (PG) = 85.1%) or three-dimensional planning (LG = 17.1%; PG = 14.9%), P = 0.778. The majority of the patients, were treated with cobalt-60. Among the patients included, 17 (PG = 9 and LG = 8) were later discontinued due to missing consultation. Among patients in the placebo group, 22 (47%) received therapeutic LLLT due to severe OM. The baseline characteristics of the patients are summarized in Table 1 .
|Characteristics||Laser group||Placebo group||P value|
|Patients – n°||47||47|
|Age – yr (SD)||0.163|
|Average||53.5 (±6.9)||55.7 (±8.6)|
|Sex – n° (%)||0.536|
|Masculine||42 (89.4)||40 (85.1)|
|Feminine||5 (10.6)||7 (14.9)|
|Primary site – n° (%)||0.107|
|Nasopharynx||7 (14.9)||2 (4.3)|
|Oropharynx||33 (70.2)||41 (87.2)|
|Hypopharynx||7 (14.9)||4 (8.5)|
|Staging – n° (%)||0.696|
|Stage I #||1 (2.1)||0|
|Stage II||8 (17.0)||6 (12.8)|
|Stage III||14 (29.8)||16 (34.0)|
|Stage IV||24 (51.1)||25 (53.2)|
|Morphology n° (%) T staging||0.107|
|T1–T2||19 (41.3)||12 (25.5)|
|T3–T4||27 (58.7)||35 (74.5)|
|N0||14 (29.8)||17 (36.2)|
|N1–N2||22 (46.8)||23 (48.9)|
|N3–N4||11 (23.4)||7 (14.9)|
|Tobacco use||37 (78.7)||42 (89.4)||0.159|
|Alcohol use||40 (85.1)||38 (80.9)||0.583|
|Radiotherapy – n° (%)||0.778|
|Cobalt60||39 (82.9)||40 (85.1)|
|Linear accelerator photons||8 (17.1)||7 (14.9)|
P values were calculated by the Student’s test.
P values were calculated by the Chi-square test.
P values were calculated by the Fisher’s exact test.
# This patient refused surgery and was treated exclusively by CRT.
Evaluation of oral mucositis
As assessed by the WHO scale, a six-fold decrease in the incidence of grades 3–4 OM was detected in the LLLT group (3 pts; 6.4%) to placebo (19 pts;40.5%), RRR:0.158 (CI 95% 0.050–0.498). In fact, only two patients (4.3%) in the LLLT group developed grade 3 OM and only one patient (2.1%) developed grade 4 OM. Moreover significant differences between the two groups for the absence of oral ulcers (grade 0–1 OM) were observed. In the LLLT group there were 59.6% (28 of 47) patients without ulcers, whereas in the placebo group there were 21.3% (10 of 47) (P < 0.001; Fig. 2 ). The use of LLLT impacted grades 3–4 OM free survival to HR of 0.139 (CI 95% 0.041–0.470; P < 0.001) ( Fig. 1-Supplementary Data ). Evaluation using the OMAS scale also revealed markedly lower values among patients: LG = 1.37 (±1.64) and PG = 2.46 (±1.52) (P < 0.001) ( Fig. 2; Table 1-Supplementary Data ). Of note a significant agreement among the evaluators occurred, with an agreement index of 89% in analyzing grade 3–4 OM according to the WHO criteria.
Assessment of oral pain intensity
Patients in the LLLT group had less severe oral pain, with significant intergroup differences in the number of cases with the degree 0 (LG = 57.5%, PG = 34%), degree 2 (LG = 8.5%, PG = 21.3%), and degree 4 (LG = 2.1%, PG = 14.9%) (P = 0.035) ( Table 2-Supplementary Data ). As a result, LLLT patients used fewer opioid analgesics (P < 0.001), and were less likely to require gastrostomy (P = 0.010) throughout the treatment ( Table 3-Supplementary Data ).
Treatment safety and disease outcome
LLLT was well tolerated and no toxicity was observed during application. Standard adverse events related to chemoradiotherapy were observed in both arms ( Table 3-Supplementary Data ). All patients will be followed up for at least five years to assess for differences in locoregional control of disease, disease-free and overall survival between the two groups. At a median follow-up of 18 months (10–48 months) differences favoring the LLLT patients were observed in locoregional disease control, progression-free (P = 0.097) or overall survival (P = 0.147; Fig. 3 and 4 of the Supplementary Data ).
Quality of life
The number of patients that answered QLQ was inferior to the number of patients randomized to each arm, mainly because the patients discontinued from the study were excluded of QLQ evaluation from that point onward. Besides, 9.5% of patients were illiterate or just refused to answer that. Missing data on QLQ were analyzed by EORTC criteria.
On the first evaluation (before 1st RT fraction) a small difference between groups was observed favoring the laser group in QLQ-H & N35, open mouth (P = 0.010), feeding tube (P = 0.012) and weight loss (P = 0.005). On the second assessment (during RT on 20th fraction) and on the last day of treatment (at the end of RT on 39th fraction) when QLQ-C30 and QLQ-H&N35 were analyzed, the LLLT group had better results, Table 4 and Quality of life results (Supplementary Data-Online Only) .
Logistic regression modeling
After adjustment for the site of primary tumor, radiotherapy energy source (linear accelerator versus cobalt), pretreatment weight loss, feeding tube insertion, pretreatment pain, and nutritional supplement, the preventive LLLT was still found to have a significant independent impact on the incidence of grade 3–4 OM with a RRR of 0.017 (CI 95% 0.002–0.092; P < 0.001).
Severe OM is a burden and an unmet medical need in HNSCC patients undergoing chemoradiotherapy and no effective preventive strategy is currently available , , , , , , and . This trial provides evidence that HNSCC patients undergoing concomitant chemoradiotherapy derive clear benefit from LLLT in the prevention of grades 3–4 OM.
As compared to placebo, LLLT led to a marked reduction in the incidence of both grades 3–4 OM, severe pain, requirement of narcotic analgesics and gastrostomy. Moreover LLLT also influenced the time to the development of grades 3–4 OM to a HR of 0.139 (CI 95% 0.041–0.470; P < 0.001). Although there has been an imbalance of oropharynx versus naso/hypopharynx sites and the LLLT group had fewer patients receiving ⩾50 Gy to the oral mucosa as compared to placebo group (n = 33 versus n = 41), particularly non-oropharyngeal tumors, multivariate analysis with a logistic regression model did show a significant benefit with preventive LLLT independent of the primary tumor site, radiotherapy energy source, pretreatment weight loss, feeding tube insertion and pretreatment pain. The intensive training and blinding of the study personnel on the assessment of OM increases the confidence in the results. In addition the observer-reported efficacy assessment matches the patients’ reports as LLLT remarkably improved the QoL, which was evaluated by two complementary and validated questionnaires. Notably preventive LLLT was safe and was not associated with toxicity or decrements in chemoradiotherapy outcomes. Considering the equipment, personnel and time required for preventive LLLT as used in this trial we believe that this is a feasible procedure in any cancer center.
In contextualizing the results of this trial, three pieces of data should be used for comparison: (a) previous trials of preventive LLLT in patients treated with chemoradiotherapy; (b) trials of preventive LLLT in patients treated exclusively with radiation; (c) studies on pharmacological approaches to chemoradiotherapy-induced OM. The design of our trial avoided confounding factors that were not adequately addressed in previous trials , , , and  such as the use of insufficient LLLT (in terms of power, energy and energy density), non-homogeneous chemoradiotherapy protocol, weekly rather than daily evaluation, exclusion of the tongue evaluation and an incomplete evaluation of the need for opioid and gastrostomy. This might explain the fact that our data contradict those obtained in a previous study which failed to detect benefit from LLLT in a similar cohort , , , and . When comparing our results with those of Gouveia de Lima et al.  , who still observed that 22% of patients showed grades 3–4 OM after receiving LLLT, it is important to note that a ten times higher power and energy were applied in our group (100 mW and 1 J versus 10 mW and 0.1 J). Similarly Carvalho et al.  and Gautam et al.  and  also used low power and observed that 60%, 29% and 23.4% of the patients showed grade 3 OM. In line with Gautam et al.  our results showed a significant reduction in the incidence of severe pain, opioids use and feeding tube insertion. In fact, a consensus is emerging that higher LLLT dosages are indeed more effective  .
Initial trials of preventive LLLT in HNSCC patients were limited to patients treated with radiation and led to promising results  . Nevertheless the methodology of assessment was an issue in those trials. Underreporting of OM may have occurred due to the lack of standardization as patients were not evaluated daily, but weekly, and OM on the tongue was not recorded , , and . Moreover since the pathobiology of OM induced by radiation alone is different from that elicited by chemoradiotherapy  comparing our data with those of others may be inaccurate.
Pharmacological approaches for the prevention of OM such as the use of benzydamine or palifermin have been explored but the efficacy is limited as compared to our LLLT trial. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology limit the administration of benzydamine to HNSCC patients receiving moderate-dose radiotherapy  , based on results showing that erythema and ulceration were decreased by only 30% as compared to the placebo. Recently treatment with palifermin, a recombinant human keratinocyte growth factor was compared to placebo in some trials  and , but its efficacy was limited since 51% and 54% grade 3 OM was still observed in palifermin arms.
Severe OM can a have a devastating effect on patients’ QoL. Here QoL questionnarie analyses showed clear benefits in the LLLT group reflecting the reduction of morbidity during treatment and reinforcing the efficacy data. The intergroup differences in patients’ complaints of emotional and physical decline illustrate how OM can contribute to pain, fatigue, difficulty in swallowing and mouth opening, mouth dryness, sticky saliva, and problems with feeding and indicates how these factors can affect the QoL of HNSCC patients. Feeding difficulties may be the greatest obstacle in the treatment of these patients  , who often require hospitalization and aggressive medical intervention for the introduction of gastrostomy, hydration, and implementation of appropriate nutritional support.
Besides its impact on QoL, severe OM can jeopardize treatment outcome due to interruptions in the course of therapy. In our study patients of both groups showed a mean weight loss of 7.8%, but no OM-related hospitalization or discontinuation of radiotherapy was required. As no differences were observed between groups regarding weight loss, hospitalizations or treatment interruptions, we believe that the pre-specified and ethics-based decision of an immediate cross-over for all patients with grades 3–4 OM from placebo group to receive 8 J/cm2 LLLT with therapeutic purposes may have precluded statistical differences in these results. Of note, all patients who had grade 3–4 OM (100%) and were crossed over improved to either grade 2 or grade 0–1.
Thus, the present trial provides evidence that LLLT is effective in preventing chemoradiotherapy-induced grades 3–4 OM in HNSCC patients. Efficacy data were corroborated by improvements seen in quality of life and disease control. Additional trials based exclusively on IMRT technique are warranted. Moreover, studies on the ideal dose of LLLT, and exploring the biological mechanism of its action may further improve the outcome of the strategy.
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a Coordination of Clinical Research, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil
b Clinical Oncology Division, INCA, Brazil
c Radiation Oncology Division, INCA, Brazil
d Nursing Division, INCA, Brazil
e Therapy and Technology Development Section, INCA, Brazil
f Private Practice, Brazil
g Head and Neck Surgery Division, INCA, Brazil
☆ Presented at the American Society of Clinical Oncology (ASCO), Chicago, IL, June 2011 and at the International Symposium of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO), Athens, June 2011.
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