Low-Level Laser for Mitigation of Low Salivary Flow Rate in Head and Neck Cancer Patients Undergoing Radiochemotherapy: A Prospective Longitudinal Study

Abstract

Objective: The present study aimed to assess the impact of low-level laser (LLL) on low salivary flow rate in patients undergoing radiochemotherapy (RT-CT) for head and neck cancer. Background data: LLL has shown efficiency in preventing hyposalivation in patients under different pathological conditions, including those undergoing RT-CT. Methods: During all RT-CT, 17 patients received laser therapy and 10 received clinical care only. An Indium-Gallium-Aluminum-Phosphorus diode laser was punctually used for intraoral (660 nm, 40 mW, 10 J/cm², illuminated area 0.04 cm², 10 sec) and extraoral irradiation (780 nm, 15 mW, 3.8 J/cm², illuminated area 0.04 cm², 10 sec), three times a week and on alternate days, for a total of 21 sessions. Unstimulated salivary flow rate was assessed before the first RT session (N0), at the 15th RT session (N15), at the last RT session (Nf), and at 30 (N30) and 90 days after the end of the oncologic treatment (N90). Results: At N15, Nf, and N30, patients treated with LLL showed significantly higher averages of salivary flow rate when compared with patients receiving clinical care only. Conclusions: LLL seems to be an efficient tool for mitigation of salivary hypofunction in patients undergoing RT for head and neck cancer.

Introduction

Radiotherapy (RT) is an important therapeutic modality for head and neck cancer (HNC). For advanced stage tumors, RT in combination with chemotherapy (CT) and/or surgery is the standard treatment, aiming for local and distant metastasis control.¹

Unfortunately, side effects of RT may occur during (acute) and after the treatment (late), interfering in patients' oral basic functions and impacting negatively on their quality of life.^1

–5 The duration and intensity of these effects are mainly determined by factors of RT such as dose per fraction, total radiation dose, irradiated volume, dose distribution in the tissue volume, and association with CT.^3,6

Despite a low mitotic activity, the salivary tissue responds quickly to radiation, probably owing to radiation-induced apoptosis. Therefore, the reduction of salivary flow rate (SFR) (or hyposalivation) is a common and persistent complication in HNC patients who have received RT with total doses of 50–70 Gy in cervicofacial fields.^6,7

The prevention and treatment of hyposalivation in patients submitted to RT could be performed by systemic stimulant agents, mechanical/gustatory stimulants, or saliva substitutes. These local stimulants and saliva substitutes only attenuate the symptoms, momentarily relieving the sensation of dry mouth (xerostomia). On the other hand, systemic agents such as pilocarpine^8,9 and bethanechol (parasympathomimetic drugs)¹⁰ are able to increase low SFR in spite of showing several undesirable effects.⁶ Amifostine, a radioprotective drug, is also available for prevention of hyposalivation; however, its high cost and side effects limit the routine use.^11,12 Other therapies such as acupuncture,¹³ cell growth factors,¹¹ hyperbaric oxygen,¹⁴ and low-level laser (LLL),^15

–18 have been proposed to prevent and/or mitigate salivary hypofunction as well.

Recently, the Multinational Association of Supportive Care in Cancer (MASCC) has updated its clinical practice guidelines for the management of mucositis secondary to cancer therapy, and it has included new recommendation in favor of LLL therapy based on its efficiency at preventing this RT-induced oral complication.¹⁹ Further, studies have reported that LLL therapy performed for oral mucositis also increases salivary output through indirect stimulation of minor and major salivary glands.^15,16 In animal models, the stimulating effect of LLL on salivary tissue has already been successfully confirmed,^20,21 but the most adequate parameters have still not been fully elucidated.

Considering these information, the aim of this study was to evaluate the effectiveness of LLL in mitigating low SFR in HNC patients during RT-CT.

Material and Methods

Study design

A prospective study with 34 patients was conducted in the Division of Radiotherapy of the Universidade Federal de São Paulo/Escola Paulista de Medicina/Hospital São Paulo (UNIFESP/EPM/HSP). The inclusion criteria were: patients undergoing megavoltage RT [three dimensional (3D) planning] for oral cavity, pharynx, larynx, and occult primary tumours, with all major salivary glands in the radiation fields. The total radiation dose ranged from 66 to 70 Gy, with 2 Gy/day fractions, and in combination with cisplatin (40 mg/m²) weekly. Radiotherapy was performed either with a linear accelerator (6 MV, Varian) or with a telecobalt-therapy (60 Co) unit (Alcion II, CGR-MeV) and administered in the right and left cervicofacial regions and supraclavicular fossae. All patients were ≥18 years of age, were able to read and sign the informed consent form, and had a Karnofsky index ≥70. The patients' exclusion criteria were: autoimmune comorbidities, diabetes mellitus, pregnancy, or use of drugs related to salivary hypofunction.

Groups and ethical considerations

Two randomized groups had been originally defined, having 17 individuals in each one. Among all these patients, only 27 could be evaluated because some of them either did not conclude all proposed procedures or died. Under these circumstances, it was considered that 17 patients received laser therapy and 10 received only clinical treatment.

This study was approved by the Research Ethics Committee of the UNIFESP/EPM/HSP - protocol 0844/10. All research subjects read and signed the informed consent form.

Clinical care procedures

All patients received oral preparation before RT-CT: periodontal and restorative treatment, dental extractions, and removal of factors that could influence in the severity of radiation-induced effects (ill-fitting prosthodontics and defective restorations). The patients were also informed about the most common oral problems and oral hygiene care. In addition, all of them were evaluated three times a week during the RT-CT and received supportive treatment, which consisted of: mouth washes with chamomile tea (5 times/day) and bicarbonate solution (3 times/day); antifungal drugs (when necessary); and daily topical application of neutral dental fluoride gel 2% (for dentulous patients).

Laser therapy

Laser therapy was performed with an Indium-Gallium-Aluminum-Phosphorus (InGaAlP) diode laser (Twin Laser - MMOptics^® Ltda, São Carlos, SP, Brazil), three times a week, on alternate days, for a total of 21 sessions. Major and minor salivary glands were irradiated punctually with the tip of the LLL device in contact with patients' tissues, always by the same dentist, and excluding the tumor region. The first laser application was performed before the beginning of the oncologic treatment and the last one was performed before the last RT session.

For extraoral application, and according to the size of the laser emission tip (0.04 cm²), the following parameters were used: 780 nm wavelength, 15 mW output power, 3.8 J/cm² dose per point, irradiation time 10 sec per point, and 0.152 J energy per point. Six points on each parotid gland and two on each submandibular gland were illuminated, resulting in an energy total of 2.432 J per session.

For intraoral application, and according to the size of the laser emission tip (0.04 cm²), the following parameters were used: 660 nm wavelength, 40 mW output power, 10 J/cm² mean dose per point, irradiation time 10 sec per point, and 0.4 J energy per point. For sublingual glands, two points on the anterior region of the oral floor were illuminated. In addition, for minor salivary glands, three points on each buccal mucosa, three on superior labial mucosa, three on inferior labial mucosa, three on the palate, one on the dorsum of the tongue, two on each lateral border of the tongue, and one on each tonsillar pillar were illuminated. An energy total of 9.6 J per session was delivered.

Saliva collection

Unstimulated sialometry in both groups was performed before the first RT-CT session (N0), at the 15th RT session (N15), at the last RT session (Nf), and at 30 (N30) and 90 days (N90) after the end of the oncologic treatment. It was performed according to protocol 97-09 of the Radiation Therapy Oncology Group (RTOG)²² and always during the same morning period. The patients were instructed to stay at least 2 h without eating, drinking, smoking, or brushing their teeth. Also, during saliva collection, they remained seated, with their eyes opened, and heads slightly bent forward.

First, the patients emptied their mouths of any saliva or mucus. Then, they accumulated saliva on the oral floor, without swallowing, during 60 sec. Then, they expectorated all the accumulated saliva into a tube graded in milliliters (mL). It was repeated four more times for a total of 5 min. Each saliva collection tube was covered and stored to rest overnight. The next day, the saliva volume was measured and the SFR per minute was calculated.

Statistical analysis

Descriptive statistics were used to summarize categorical data (gender, age, ethnicity, alcohol abuse, tobacco abuse, tumor primary site, tumor histopathologic type, tumor staging, surgery, and total radiation dose).

The SFR of the both groups was submitted to statistical analysis. The Friedman's test was used for intragroup comparison. Comparison between the two groups, at the different time periods, was performed through the Mann–Whitney test. The p value was set at 0.05.

Results

General

The patients' demographic characteristics are summarized in Table 1. The ages of the patients treated with laser therapy ranged from 35 to 74 years (mean: 56.6) and the age of those treated clinically ranged from 51 to 68 years (mean: 58.5).

Table 1.

Patients' Demographic Characteristics

	Laser therapy		Clinical care only		Total
Demographic characteristics	Patients	%	Patients	%	Patients	%
Gender
Male	15	88.2	9	90	24	88.9
Female	2	11.8	1	10	3	11.1
Ethnicity
Leukoderma	12	70.6	8	80	20	74.1
Pheoderma	3	17.6	2	20	5	18.5
Melanoderma	2	11.8	0	0	2	7.4
Alcohol abuse
Previous	14	82.4	8	80	22	81.5
Current	3	17.6	1	10	4	14.8
Nonexistent	0	0	1	10	1	3.7
Tobacco abuse
Previous	13	76.5	8	80	21	77.8
Current	3	17.6	2	20	5	18.5
Nonexistent	1	5.9	0	0	1	3.7

The characteristics of tumors and treatments are also summarized in Table 2.

Table 2.

Characteristics of the Tumors and Treatments

	Laser therapy		Clinical care only		Total
Characteristics	Patients	%	Patients	%	Patients	%
Histological type of the tumor
Squamous cell carcinoma	17	100	10	100	27	100
Primary site of the tumor
Pharynx	10	58.8	8	80.0	18	66.7
Larynx	3	17.6	0	0	3	11.1
Oral cavity	2	11.8	0	0	2	7.4
Occult primary tumor	2	11.8	2	20.0	4	14.8
Stage of the tumor
IV	12	70.6	9	90.0	21	77.8
III	4	23.5	0	0	4	14.8
I	1	5.9	1	10.0	2	7.4
Surgery (unilateral neck dissection)
No	13	76.5	6	60.0	19	70.4
Yes	4	23.5	4	40.0	8	29.6
Total radiation dose
70 Gy	15	88.2	7	70.0	22	81.5
66 Gy	2	11.8	3	30.0	5	18.5

Unstimulated SFR

Before the beginning of the treatment (N0), there was no statistical difference between the groups (p = 0.1833).

A significant reduction in the SFR occurred in both groups at all time periods (N15, Nf, N30, N90) (laser, p = 0.0009; clinical care only, p = 0.0005).

Data showed that the mean SFR of patients treated with laser was significantly higher when compared with patients treated with clinical care only, at N15 (p = 0.0159), Nf (p = 0.0149), and N30 (p = 0.0239) (Fig. 1).

FIG. 1.

Salivary flow rates. Mean unstimulated salivary flow rates of patients treated with laser therapy and patients treated with clinical care only, at baseline (N0), at the 15th radiotherapy (RT) session (N15), at the last radiochemotherapy (RT-CT) session (Nf), and at 30 (N30) and 90 days (N90) after the end of oncologic treatment. (95% confidence intervals).

At N90, the mean SFR of the group treated with laser therapy was almost twice of the other; however, this was without statistical significance (p = 0.3796) (Table 3).

Table 3.

Mean Unstimulated Salivary Flow Rates of Patients Treated with Laser Therapy and Patients Treated with Clinical Care Only, at Baseline (N0), at the 15th RT Session (N15), at the Last RT-CT Session (Nf), and at 30 (N30) and 90 Days (N90) After the End of Oncologic Treatment

Unstimulated sialometry	N0 (mL/min)	N15 (mL/min)	Nf (mL/min)	N30 (mL/min)	N90 (mL/min)
Laser therapy	0.54	0.42	0.39	0.28	0.23
Clinical care only	0.54	0.18	0.17	0.11	0.13
p Value	0.1833	0.0159^*	0.0149^*	0.0239^*	0.3796

Statistical significance: p value ≤0.05.

RT, radiotherapy; RT-CT, radiochemotherapy.

Discussion

Hyposalivation may cause secondary effects such as decreased perception of taste, difficulty in mastication and deglutition, greater predisposition toward oral fissures and ulcerations, increased rate of dental caries and periodontal disease, changes in the composition of the oral microflora, and increased risk of maxillary osteoradionecrosis and esophageal lesions.^6,7 It is also proposed that the decreased SFR and the xerostomia (subjective sensation of dry month) negatively impact the quality of life of patients treated with RT-CT.^1,7 Therefore, a better understanding of preventive methods and available treatments for salivary hypofunction are necessary and opportune.

Our results showed a significant reduction in the mean SFR at the different assessment periods, in both groups. At N15, Nf, N30, and N90, the mean SFR of patients only receiving clinical care decreased ∼0.36 mL/min (66.7%), 0.37 mL/min (68.5%), 0.43 mL/min (79.6%), and 0.41 mL/min (75.9%), respectively. These data corroborate articles that have reported low SFR in patients during and after RT-CT with no preventive method for hyposalivation.^23,24 It is also known that an adequate amount of saliva is extremely important because it impacts positively on post-RT mucosal reactions.²⁴

In patients treated with LLL therapy, a reduction in the SFR was also expected. The mean decrease was 0.12 mL/min (22.2%) at N15, 0.15 mL/min (27.8%) at Nf, 0.26 mL/min (48.1%) at N30, and 0.31 mL/min (57.4%) at N90. Fortunately, these decreases occurred in a much less intense manner, suggesting the benefits of LLL therapy. This group had significant higher mean values at N15, Nf, and N30, and maintained the mean SFR >0.2 mL/min (no or mild hyposalivation). On the other hand, patients treated only clinically had a mean SFR between 0.1 and 0.2 mL/min (moderate hyposalivation).⁷

At the final assessment (N90), patients treated with LLL presented a mean SFR twice that of those treated only clinically; however, a statistical significance could not be obtained. Obviously, we should consider both the restricted number of patients and the numerical difference between groups which, unfortunately, occurred during the study.

The exact mechanisms responsible for LLL effects on salivary tissue remain poorly understood. It is believed that LLL increases local circulation (vasodilation), induces glandular cell proliferation, improves cell respiration and adenosine triphosphate (ATP) synthesis, and stimulates growth factor releasing and cytokinesis.¹⁷ This type of laser usually has energy levels lower than the binding energy of biological molecules and DNA and, consequently, it is unable to break chemical bonds and induce mutations.¹⁵ Data on the effects of LLL on the proliferative ability of dysplastic and neoplastic cells are inconsistent, probably because of the lack of standardization of the study designs. An article observed, in vitro, no proliferative or antiapoptotic effects of LLL on epithelial neoplastic cells.²⁵ On the other hand, in vitro studies demonstrated that LLL could aggravate oral cancer cellular behavior, facilitating its proliferation and invasion.^26,27 Despite this disagreement, we choose to avoid the laser applications in the tumor areas and lymph nodes affected by the disease.

Our laser protocol was based on articles with different approaches. In one such study, it was reported that intraoral LLL therapy for radiation-induced mucositis attenuated the low SFR and xerostomia levels.¹⁶ Other studies showed that intraoral LLL therapy during RT-CT with the purpose of mitigating the unstimulated SFR was extremely efficient.^15,18 Further, for extraoral applications, we preferred employing a longer laser wavelength because of its deeper penetration into biological tissues.

To the best of our knowledge, this is the first time that a combination of different wavelengths and extra- and intraoral laser applications is specifically used with the aim of attenuating the low SFR in HNC patients undergoing RT-CT. However, it is important to highlight that direct comparisons between our data and those present in the literature cannot be made, because each study has its own design, laser parameters, treatment characteristics, and groups of patients.

Conclusions

LLL seems to be a promising and efficient agent for mitigation of salivary hypofunction in HNC patients undergoing RT-CT.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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