Treatment of Oral Leukoplakia With Carbon Dioxide and Potassium-Titanyl-Phosphate Lasers: A Comparison

J Oral Maxillofac Surg 68:597-601, 2010

Treatment of Oral Leukoplakia With Carbon Dioxide and Potassium-Titanyl-Phosphate Lasers: A Comparison Bernard Lim, BDSc(Hons), MBBS(Hons), Grad DipOMS,* Andrew Smith, BDS, MDSc, FDSRCS(Eng), FDSRCPS, FRACDS(OMS),† and Arun Chandu, BDSc, MBBS(Hons), MDSc, FDSRCS(Eng), FRACDS(OMS)‡ Purpose: To determine whether the treatment of oral leukoplakia with potassium-titanyl-phosphate

(KTP) lasers versus CO2 lasers results in lower recurrence rates. Retrospective data were collected from the records of 30 patients (mean age 75.6 years) with 35 primary oral leukoplakia who had their lesions ablated by KTP laser, and 45 patients (mean age 59.9 years) with 59 primary oral leukoplakia who had CO2 laser treatment. The recurrence rates of lesions between these 2 groups was then compared. Results: A statistically significant (P ⫽ .049) reduction in recurrence rates for those patients treated with KTP lasers versus CO2 lasers was found. Conclusion: The use of KTP lasers for the treatment of oral leukoplakia may result in lower recurrence rates than when using CO2 lasers. Crown Copyright © 2010 Published by Elsevier Inc on behalf of American Association of Oral and Maxillofacial Surgeons. All rights reserved. J Oral Maxillofac Surg 68:597-601, 2010 Materials and Methods:

The World Health Organization has defined oral leukoplakia as “a white patch or plaque of the oral mucosa that cannot be characterized clinically or pathologically as any other disease.”1 The clinical significance of these lesions is that they can undergo malignant transformation. According to Schepman et al,2 nearly 50% of all oral squamous cell carcinoma (SCC) cases are associated with, or preceded by, clinically detectable premalignant lesions such as oral leukoplakia. The percentage of lesions that undergo malignant transformation has varied widely among studies, from 6% to 23% during an average 20-year follow-up period.3-8 As a result, few data are available to recommend conservative or noninterventional management strategies for these lesions.9

Many different treatment modalities for oral leukoplakia have been reported. Nonsurgical methods include the topical application of bleomycin, systemic administration of 13-cis-retinoic acid and systemic ␤-carotene.10,11 Although these treatments can result in the resolution of leukoplakia in a proportion of patients, they do not affect the rates of malignant transformation compared with placebo groups.10-12 Other disadvantages that have been identified include patient side effects and a high relapse rate once the therapies were discontinued.13 Surgical modalities for the treatment of oral leukoplakia include scalpel excision,14 cryotherapy,15 electrocoagulation,16 and laser therapy. Ben-Bassat et al17 first described laser therapy for the treatment of oral leukoplakia in 1978. Since then, many studies have found it to be a safe and effective treatment modality. Many different laser types have been used in the treatment of oral leukoplakias, including the carbon dioxide (CO2), neodymium:yttrium-aluminum garnet (Nd:YAG), argon, and potassium-titanylphosphate (KTP) lasers.18,19 The benefits of laser treatment include the creation of a bloodless surgical field and thus improved visualization and accuracy, reduced postoperative pain owing to the cauterization of nerve endings and blood vessels, and limited scarring and contraction owing to the limitation of damage to the surrounding tissues.20 The disadvantages of laser treatment include the inability to obtain samples for histologic analysis when ablative techniques are used,

*Registrar, Department of Oral and Maxillofacial Surgery, Royal Dental Hospital of Melbourne, Carlton, Victoria, Australia. †Consultant, Melbourne Dental School, University of Melbourne, Carlton, Victoria, Australia. ‡Associate Professor, Department of Oral and Maxillofacial Surgery, Western Hospital, Footscray, Victoria, Australia. Address correspondence and reprint requests to Mr Chandu: Department of Oral and Maxillofacial Surgery, Western Hospital, Footscray, Victoria, Australia; e-mail: [email protected] Crown Copyright © 2010 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons. All rights reserved. 0278-2391/10/6803-0016$36.00/0 doi:10.1016/j.joms.2009.03.028

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598 and the need for additional safety measures during surgery. The present study was a follow-up study comparing the data obtained from an earlier study using CO2 lasers21 with more recent data examining the outcomes of patients treated with KTP lasers. The aim of the present study was to assess the differences in disease-free survival of patients treated with either a KTP or CO2 laser for oral leukoplakia.

Materials and Methods The data were collected retrospectively from the records of patients with oral leukoplakia who had been treated with KTP laser therapy at Austin Health, Melbourne, Victoria, between 2002 and 2007. These data were then compared with the data obtained from the records of patients treated by CO2 laser at the Austin Health between 1995 and 2002. The findings of those treated by CO2 laser were previously reported.21 The exclusion criteria included patients with nonwhite patch lesions such as warts, biopsy-proven SCC, and vascular lesions. The inclusion criteria included all patients with clinical oral white patches treated with a laser. Incisional biopsies were taken before definitive laser treatment for histologic examination. The Human and Research Ethics Committee at Austin Health approved the present study. All patients underwent laser treatment under general anesthesia with nasotracheal intubation. The operative site was isolated using saline-moistened abdominal packs to avoid damage to the surrounding anatomic structures. Laser ablation was performed in all patients. The area to be ablated was initially outlined, and then multiple rasters were performed, with ablation continuing down to the submucosal layer. Two different types of laser systems were used in this patient population: the KTP and CO2 lasers. The KTP laser was a Laserscope Surgical Laser System (model No. 813, Aura Laserscope, San José, CA). The power level used for ablation was 5 W in continuous mode. Delivery was by way of a Laserscope Endostat 0.6-mm diameter flexible optic fiber probe (Endostat, San José, CA). The CO2 laser was a Sharplan 743 (Laser Industries, Tel Aviv, Israel) with power levels varying from 10 to 15 W in continuous mode. Local anesthetic was then injected for postablation pain control, and the patients were sent home with a topical anesthetic mouth rinse and oral analgesia. All patients were then reviewed on a regular basis in the outpatient clinic to monitor the outcome. The data analyzed included the demographic details, as well as other risk factors, including smoking and alcohol consumption. The examination data included the macroscopic appearance of the lesion, sites of the lesions, and the histologic findings of the

CO2 AND KTP TREATMENT OF ORAL LEUKOPLAKIA

initial biopsy specimen. Finally, the interval from laser treatment to recurrence/malignant transformation was noted, as were any complications arising from treatment. Recurrence was defined as the reappearance of leukoplakia in a previously laser-treated site. Once recurrence was noted, the interval in months that had elapsed since the initial laser treatment was noted and recorded as the disease-free interval. Lesions that appeared at a site distant from the initial laser treated field were not counted as recurrences. Malignant transformation was defined as the appearance of SCC at the site of laser treatment. The results are presented descriptively. KaplanMeier curves with log-rank tests were used to assess the difference between the 2 laser groups. Because of the low numbers of patients undergoing malignant transformation of the lesions treated, recurrence in relation to disease-free survival included recurrence of the leukoplakia, as well as malignant transformation. All statistical analysis was performed using StatView, version 5 (SAS Institute, Cary, NC). P less than .05 was taken as significant.

Results A total of 75 patients treated with laser therapy for oral leukoplakia laser were eligible for inclusion in the present study. Of the 75 patients, 30 were treated with a KTP laser and 45 with a CO2 laser. The mean patient age for both groups was 67.5 years, with the mean age of the KTP laser group greater than that of the CO2 group (75.6 versus 59.9 years). Although a male predilection was found in both groups, this was more pronounced in the CO2 cohort (53% men in the KTP group and 64% in the CO2 group). Otherwise, the 2 population groups were very similar, with an almost equal proportion of smokers, ex-smokers, and alcohol drinkers in both cohorts (Table 1). Because of the multiple sites requiring treatment in some CO2 patients, the total number of sites treated was 35 in the KTP group and 47 in the CO2 group. The most common sites affected by leukoplakia in both groups were the floor of mouth, lip, tongue, and buccal mucosa. The palate and alveolus were less commonly affected in this population (Table 2). Macroscopically, most lesions were homogenous leukoplakias, with a much smaller proportion of erythroleukoplakias and erythroplakias (Table 3). The histologic findings on biopsy revealed varying degrees of dysplasia, carcinoma in situ, actinic changes, and epithelial hyperplasia (Table 4). Of the treated lesions, 3 in the CO2 group and 4 in the KTP group underwent malignant change during the observation period. Of these 7 malignancies, 6 had developed from lesions shown to exhibit moderate or se-

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LIM ET AL

Table 1. DEMOGRAPHIC DATA OF PATIENTS TREATED

Variable Age (yr) Mean Range Gender (n) Male Female Positive smoking history (%) Current smokers (%) Alcohol use (%)

Table 3. MACROSCOPIC APPEARANCE OF ORAL LEUKOPLAKIA

KTP Laser

CO2 Laser

Appearance

KTP Laser (n)

CO2 Laser (n)

75.6 39-90

59.9 21-79

Leukoplakia Erytholeukoplakia Erythroplakia

28 4 3

44 2 1

16 14 70 23 23

29 16 71 24 22

Abbreviations: KTP, potassium-titanyl-phosphate; CO2, carbon dioxide. Lim et al. CO2 and KTP Treatment of Oral Leukoplakia. J Oral Maxillofac Surg 2010.

vere dysplasia on the initial biopsy, and 1, in the CO2 group, had developed from an area of actinic change. No significant difference was found in the follow-up times of the 2 groups (41 months [range 8 to 80] for the KTP group; and 43 months [range 2 to 102] for the CO2 group). The crude recurrence rate for the KTP and CO2 groups was 25% and 39.5%, respectively. The cumulative disease-free survival for both laser groups is reported in Table 5. The KaplanMeier analysis with log-rank tests revealed a statistically reduced recurrence rate in the KTP group compared with the CO2 group (P ⫽ .049; Fig 1). The average interval to recurrence was 26.16 months (range 2 to 80) in the CO2 group and 30.7 months (range 4 to 76) in the KTP group. Few complications were reported in either group. One patient in each group reported prolonged pain after laser ablation, one in the CO2 group reported chronic headaches, and one in the KTP group reported temporary taste changes after ablation of a tongue leukoplakia.

Discussion Most recent reported studies have examined the efficacy of CO2 lasers in the treatment of oral leuko-

Abbreviations as in Table 1. Lim et al. CO2 and KTP Treatment of Oral Leukoplakia. J Oral Maxillofac Surg 2010.

plakia.3,4,7,15,16,18-20 A large retrospective study by van der Hem et al22 used the CO2 laser to treat 282 leukoplakias in 200 patients and achieved a cure rate of 89% during a mean follow-up period of 52 months. Thomson and Wylie9 reviewed 57 consecutive CO2 laser-treated patients. They found that 76% remained disease free during a mean 18-month follow-up period, and 7% of those who experienced recurrence developed oral SCC. A recent study by Chandu and Smith21 examined the outcome of leukoplakia treated with CO2 laser ablation. That study, which included 43 patients with a total of 73 primary oral leukoplakias, found that the disease-free survival rate was 55.4% at 3 years, which decreased to 33.9% after 5 years. Therefore, one can see that the recurrence rates of leukoplakia treated with CO2 laser is quite variable, with recurrence rates of 7.7% to 66% reported.23-27 Factors, such as surgical technique, patient factors, and different patient follow-up periods, might account for this wide range in recurrence rates.23 However, another factor that might influence the disease outcome is the type of laser used for the treatment of oral leukoplakia. Few studies have reported on the use of KTP laser for the treatment of oral leukoplakia. Ishii et al19 examined the use of CO2, Nd:YAG, and KTP lasers for the treatment of oral leukoplakia. However, the KTP lasers were used to excise, and not ablate, lesions. Furthermore, no comparison was made in their study of the differences in

Table 4. HISTOLOGIC FINDINGS OF ORAL LEUKOPLAKIA TREATED WITH LASER THERAPY

Table 2. SITE OF LEUKOPLAKIA TREATED

Site

KTP Laser

CO2 Laser

Floor of mouth Lip Tongue Buccal mucosa Palate Alveolus

13 6 7 6 1 2

10 12 8 11 6 0

Abbreviations as in Table 1. Lim et al. CO2 and KTP Treatment of Oral Leukoplakia. J Oral Maxillofac Surg 2010.

Finding

KTP Laser (n)

CO2 Laser (n)

Mild dysplasia Moderate dysplasia Severe dysplasia Carcinoma in situ Lichenoid changes Epithelial hyperplasia Actinic changes

16 8 4 3 0 4 0

26 6 6 3 2 2 2

Abbreviations as in Table 1. Lim et al. CO2 and KTP Treatment of Oral Leukoplakia. J Oral Maxillofac Surg 2010.

600

CO2 AND KTP TREATMENT OF ORAL LEUKOPLAKIA

the efficacy of the 3 laser types when treating oral leukoplakia. The difference between CO2 lasers and KTP lasers is the wavelength at which they deliver energy, and this accounts for their clinical properties. CO2 lasers generate energy at a wavelength of 10.6 ␮m and have been found in rat tongue epithelia to result in a microscopic damage zone to an average depth of 250 to 500 ␮m.28 CO2 lasers cause vaporization of intracellular water and the destruction of cell membranes, and the thermal damage to surrounding tissues is minimal.29 KTP lasers, in contrast, deliver energy at 532 nm and, because of this shorter wavelength, passes through water and penetrates deeper into the tissues, creating more thermal scatter.30 This leads to a larger area of coagulative damage to surrounding tissue, thus potentially increasing postoperative pain.31 Recurrences will also occur if deep nests are left in situ after any surgical treatment. Therefore, it is essential that the full thickness of the epithelium is removed during ablative laser surgery.32 Thus, we hypothesized that the KTP laser would be more effective than the CO2 laser in preventing recurrences of oral leukoplakia, owing to its greater tissue penetrance and greater effect on the surrounding tissues owing to the thermal scatter. A number of other factors, however, can also contribute to the recurrence of leukoplakia. Frame33 hypothesized that the recurrence of leukoplakia might be due to the migration of new epithelium from surrounding unstable mucosa. As a result, some investigators have advocated the use of vital staining using toluidine blue34-36 or iodine37 before laser therapy to ensure the absence of dysplastic mucosa at the wound margins. However, other investigators have found that vital staining was of little benefit38 and that vital staining could also alter the amount of energy absorbed from the laser, reducing its effectiveness.19 The recurrence of leukoplakia could also result from the concept of field change or cancerization. Recent studies have examined the risk of developing oral SCC at a molecular (genetic) level.39-41 It is thought that a progressive loss of heterozygosity in the genetic sequence of specific chromosomes in oral

Table 5. RECURRENCE RATES

Cumulative Survival (mo)

KTP (95% CI)

CO2 (95% CI)

12 36 60

87.1% (75.3-98.7) 80.4% (66.3-94.5) 70.3% (48.2-92.5)

70.0% (55.7-84.2) 57.5% (41.3-73.7) 35.9% (11.5-60.4)

Abbreviations: CI, confidence interval; other abbreviations as in Table 1. Lim et al. CO2 and KTP Treatment of Oral Leukoplakia. J Oral Maxillofac Surg 2010.

FIGURE 1. Cumulative survival for KTP and CO2 laser treatment. Lim et al. CO2 and KTP Treatment of Oral Leukoplakia. J Oral Maxillofac Surg 2010.

mucosal tissue leads to worsening degrees of dysplasia and, eventually, invasive SCC.42,43 These genetic changes could be widespread, hence the term “field change,” and triggered by environmental factors such as smoking and alcohol use.44 Oral epithelium within the area of field change could appear clinically normal. Therefore, in such individuals, it might be that recurrence is inevitable, regardless of the treatment modality used because the surgical margins might be within an area of field change.9,21 The limitations of the present study were that it was retrospective in nature, and the sample sizes were modest. Nevertheless, few studies have directly compared the efficacy of 2 different laser types in the treatment of oral leukoplakia. Our results have demonstrated a statistically significant reduction in recurrence rates in those treated with KTP laser ablation compared with those treated with CO2 laser ablation. This reduction in recurrence might have resulted from the different patterns of thermal damage between the KTP and CO2 laser.

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