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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 34  |  Issue : 4  |  Page : 409-413

Comparison of efficacy of topical application of bleomycin with adjuvant antioxidants vs. Topical curcumin oral gel with adjuvant antioxidants in the treatment of oral leukoplakia


Department of Oral Medicine and Radiology, Tamilnadu Government Dental College And Hospital, Chennai, Tamil Nadu, India

Date of Submission11-Jul-2022
Date of Decision19-Nov-2022
Date of Acceptance23-Nov-2022
Date of Web Publication09-Dec-2022

Correspondence Address:
A I Samu Fathima
No. 37, Raju Street, West Mambalam, Chennai.33, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.jiaomr_201_22

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   Abstract 


Introduction: Oral leukoplakia (OL) is an oral premalignant disorder (OPMD) defined as a white plaque of questionable risk, and the diagnosis is by exclusion. Aim: We aimed to compare the effectiveness of topical bleomycin with that of topical curcumin in patients with oral leukoplakia (OL). Materials and Methods: Bleomycin was assigned for group A and curcumin for group B patients. Both the drugs were applied topically with adjuvant oral antioxidants for both groups. Results: Group A (n = 10) patients showed partial to complete resolution of the leukoplakic lesions with a P value of 0.01, whereas in group B (n = 10) patients, resolution of the clinical lesion was not substantial, but a reduction of the erythroid component was observed along with histopathological improvement of dysplasia with a P value of 0.01. Conclusion: Comparatively, bleomycin was more efficient in producing clinical and histopathologic resolution of OL than curcumin.

Keywords: Dimethyl sulfoxide, oral leukoplakia, oral potentially malignant disorders
Key Message: Bleomycin could serve as a routine therapeutic drug in the treatment of oral leukoplakia owing to its efficacy and cost-effectiveness.


How to cite this article:
Fathima A I, Manoharan G V. Comparison of efficacy of topical application of bleomycin with adjuvant antioxidants vs. Topical curcumin oral gel with adjuvant antioxidants in the treatment of oral leukoplakia. J Indian Acad Oral Med Radiol 2022;34:409-13

How to cite this URL:
Fathima A I, Manoharan G V. Comparison of efficacy of topical application of bleomycin with adjuvant antioxidants vs. Topical curcumin oral gel with adjuvant antioxidants in the treatment of oral leukoplakia. J Indian Acad Oral Med Radiol [serial online] 2022 [cited 2023 Feb 3];34:409-13. Available from: http://www.jiaomr.in/text.asp?2022/34/4/409/363023




   Introduction Top


Oral cancer is the most common cancer in India among men (11.28% of all cancers) and the fifth most frequently occurring cancer among women (4.3% of all cancers).[1] Oral cancer is the third most frequent cancer among men and women in India, with an annual incidence of around 77,000 cases and 52,000 deaths yearly.[2] The concern of oral cancer in India is higher since the reported 70% of cases usually present in the later stages, posing difficulty in treatment despite recent advances in treatment modalities and poor prognosis with a 5-year survival rate of around 20% (American Joint Committee on Cancer).[2]

Oral potentially malignant disorders (OPMD).constitute a group of oral mucosal lesions with an increased risk of malignant transformation. Early diagnosis results in a better prognosis and survival rate of up to 90% in a 5-year follow-up period.[2]


   Materials and Methods Top


Patient selection was made from the outpatients who reported to the Department of Oral Medicine and Radiology between the year 2019–2021, and informed consent was obtained from all the patients undergoing therapy. Ethical approval was obtained from the Institutional Review Board (IEC reference no: 4/IRB/2019) with standards per the revised Helsinki declaration. The sample size was calculated with a power of 80% using G power software.

Patients were divided randomly into two groups, where group A (study group) patients received topical bleomycin with antioxidant supplements (n = 10) and group B (control group) received topically applied curcumin gel with antioxidant supplements (n = 10). After the clinical and hematologic investigations, liver and renal function tests (urea, creatinine, protein, uric acid, and electrolytes) were performed.

Methodology

Inclusion criteria

  • Clinically and histopathologically proven cases of oral leukoplakia.
  • Age 20–60 years


Exclusion criteria

  • Immunocompromised patients.
  • Histopathologically has proven carcinoma cases.


Group A

Bleomycin solution was obtained by mixing the bleomycin (Tradename: BLEOCEL, Celon labs Pvt Ltd, Hyderabad, Telangana) 15 IU vial powder with dimethyl sulfoxide solution (DMSO) to obtain a concentration of 1% (w/v).

Each patient under group A was seen daily for 14 days, with the weekend (Sunday) excluded. Patients were advised to intake adjuvant antioxidant capsules twice daily (smFibro, Warren, Indoco, Thane). The lesion was cleaned with a ball of dry cotton wool and ensured dryness over the lesion. Then, a new cotton pledget dipped in the bleomycin powder mixed in dimethyl sulfoxide solution made in a concentration of 1% was applied continuously, focusing the lesion area. After 5–10 min of doing the same procedure, the patient was asked to rinse the mouth with water. During the complete five minutes application, 0.5–1 ml of solution was used for the patient.

Group B

The patient is advised to topically apply the curcumin oral gel (Tradename: CURENEXT, Abbot laboratories) six times daily with adjuvant antioxidant capsules (smFibro, Warren, Indoco, Thane) twice daily supplementation.

Both the groups were evaluated for clinical improvement of either hyperkeratosis or the degree of dysplasia in the follow-up histopathological examinations done after an interval of three months of the therapy. Scoring criteria were based on the grading system given by Smith and Pindborg's epithelial atypia index.

Statistical analysis

Statistical analysis was done by SPSS version 18.0 (IBM statistics). Mann–Whitney U test and Wilcoxon signed-rank test were employed in this study. A P value less than 0.05 was considered statistically significant.


   Results Top


Out of the total of 23 cases of oral leukoplakia selected for the study, three patients dropped out, making the sample size 20. The mean age distribution of the patients is 45.15, and the standard deviation is 11.37. Out of the 20 patients, 17 were males, and three were females, with tobacco usage history in only one out of the three female patients, whereas tobacco history was there in all the male patients enrolled [Chart 1] and [Chart 2].



Type distribution and histopathology

Under the group A category, 60% of the cases had hyperkeratosis, 20% had mild dysplasia, and 20% showed moderate dysplasia. Under group B, 20% of cases exhibited hyperkeratosis, 40% had mild dysplasia, and the remaining 40% showed moderate dysplasia upon statistical observation after randomization [Chart 3], [Table 1] and [Table 2].

Table 1: Comparison of post-treatment clinical resolution between the groups

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Table 2: Comparison of post-treatment histopathologic grading between the groups

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A significance P value (0.01) was obtained for clinical resolution, which cannot be correlated histopathologically for the bleomycin group. The fact behind this is that the post-treatment biopsy was not taken from the clinical resolution site but from the remaining leftover lesion area to assess the degree of histopathologic improvement using the Wilcoxon signed-rank test.

Using the Wilcoxon signed-rank test, even though the P value for clinical resolution of the curcumin group was not significant, a P value of 0.01 was obtained for histopathological resolution in group B patients. Mild and moderate dysplasia downgraded into hyperkeratosis with significant improvements in terms of reduction in erythema and re-epithelialization being the possible contributory factors [Figure 1] and [Chart 4], [Chart 5], [Chart 6].
Figure 1: (a) Group B (Curcumin) patient post- incisional biopsy pre-treatment image (b) Same patient post- treatment (curcumin) image showing 25% lesion resolution with marked reduction of erythema and showing re-epithelialization without any appreciable clinical resolution

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Interpretation

The greater clinical resolution was achieved in the bleomycin group when compared to curcumin, where there was marked downgrading of dysplasia into hyperkeratosis and greater histopathologic improvement even when clinical lesion size resolution was not substantial, and this was confirmed with statistics.


   Discussion Top


Oral leukoplakia, despite the availability of various pharmacological and surgical therapies, remains a challenge due to higher recurrences and risk of malignant transformation. Up to 67% of OSCCs are preceded by oral leukoplakia,[3] and in the long-term follow-up, 0–3% underwent hyperplastic changes, and up to 30% of mildly dysplastic lesions underwent a malignant transformation.[4],[5] Dysplasia is an independent factor for malignant transformation; history reveals that any lesion, even those without dysplasia, can show malignant transformation if left untreated, and intervention becomes essential for the same.

Of all the 20 patients, three had erythroleukoplakia, two had verrucous, nine had homogenous, and six exhibited non-homogenous leukoplakias. Out of the three erythroleukoplakia cases, two cases were included randomly in group B (curcumin). One patient recruited under group A (Bleomycin) had a history of the lesion for the past three years after cessation of the habit and had already been treated multiple times with topical curcumin and steroid therapy and responded poorly with absolutely no results. During the 14 days of bleomycin therapy, the patient responded well with visible resolution of the lesions in the buccal mucosa bilaterally with a subjective VAS score reduction from 10 to 4. But in the follow-up period, relapse of the lesion ensued slowly, with the lesion severity reverting to the pre-treatment level. The patient was unwilling to use any other surgical therapy. One patient (in group A) showed a reduction in the erythema of the lesion with an improved subjective VAS score from 10 to 5 with very minimal lesion size reduction. Still, it was noteworthy to mention that the disappearance of the erythema of the lesion was indicative of re-epithelialization and concurrent reduction in the degree of dysplastic changes with a down gradation into the acanthomatous epithelium. For the third patient (in group B), partial excision of the lesion was done during incisional biopsy since the lesion was over the lateral border of the tongue. The remaining lesion was treated with topical curcumin therapy with no evident clinical changes post-treatment apart from the resolution of erythema with dysplasia reduction from moderate to mild. The resolution of inflammatory signs achieved by curcumin therapy concords with the previous study by Chainani-Wu.[6]

Out of the two verrucous leukoplakias, one in group A and the other in group B, none responded to therapy and hence were referred to the department of oral and maxillofacial surgery for the surgical excision in toto.

Regarding the cases with homogenous leukoplakias, out of the total nine cases, seven were in group A, and two in group B. Two out of the six patients in group A showed more than 50% lesion resolution in terms of size as well as a reduction in the thickness of the lesion. Two patients had a whopping reduction of more than 75% both in terms of size and thickness as said earlier. One of the patients showed a reduction of more than 25% in the size [Figure 2]. Still, the thickness of the lesion had reduced far better than the size, as if only a faint white patch had been left out post-therapy, which was the result of peeling off the lesional epithelium as described by Hammersley et al.[7] and thinning off of the keratotic epithelium as confirmed by Wong et al.[8] The remaining two patients had no change post-treatment. Most patients showed significant clinical and histopathological resolution, as described by Malmström et al.[9]
Figure 2: (a) Group A (Bleomycin) patient post- incisional biopsy pre-treatment image (b) Same patient post- treatment (bleomycin) image showing more than 75% lesion resolution

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On analyzing other variants of non-homogenous leukoplakia, out of the total six cases, two were in the bleomycin group, and the rest were in the curcumin category. The bleomycin category showed improved clinical as well as histopathological resolution, which is in concordance with another study done with 1% bleomycin by Epstein,[10] whereas histopathologic resolution was seen in most of the curcumin-treated patients. Follow-up period for all these patients was a minimum of four months and a maximum of two years (for patients unwilling to undergo further modalities of therapy). Even though the sample size of this study was affected by the ongoing COVID pandemic, the overall results show that topical therapy with 1% bleomycin is more effective than topical curcumin therapy.

Those patients who seemingly had resolution of the lesion with bleomycin were documented each day with photographs taken at the same angle and under the same light settings. Peeling away from the homogenous white patch was seen and documented in all group A patients of the homogenous category during the treatment period. Bleomycin appeared to have shown better clinical resolution of the lesion ranging from 25–75% lesion size reduction. It is associated thinning of the white plaque, as confirmed in the study by Hammersley et al.[7] Similar studies were already done with the dimethyl sulfoxide (DMSO) carrier solution alone as a placebo control revealed no evident resolution of OL, which further confirms the efficacy of bleomycin as the principal effective drug in the treatment of OL. Assuming that the total absorption of bleomycin per patient is 15 mg, toxicity rarely ensues since the dose of bleomycin used in the treatment of lymphomas that imposes toxicity is far greater than the current dosage, and that too when applied topically, practically most of the excess solution from the cotton pellet drips off which has to be wiped off making the total absorption level even lesser than the allotted amount of solution per day for each patient. Curcumin was identified by the patients as a sweet-tasting gel that, upon application, had no subjective discomfort. All of the patients were asked to keep the curcumin gel in a handy place so as to remember for each application.

The following overall clinical lesion resolution was obtained: In group A patients, greater than 75% resolution was achieved in 20% of cases, greater than 50% resolution in 40% of cases, and greater than 25% resolution in 20% of cases and no resolution in 20% of cases was observed. In the histopathological aspect, 20% of cases in mild and moderate dysplasia categories, respectively, were downgraded into hyperkeratosis in group A patients. In group B patients, 40% of mild and moderate dysplasia cases, respectively, were downgraded into hyperkeratosis.

Limitations of the study

  • Post-treatment histopathologic examination was not taken from the site of clinical resolution.
  • Absence of specific criteria to measure the reduction in the thickness of the hyperkeratotic lesional epithelium.


Future prospects of the study

  • Bleomycin, when applied in a higher concentration topically in the form of a solution or innovative gel/patches, can be tried in treating OL with hopes of better resolution than achieved in our study.



   Conclusion Top


The results of our current study have proved that topical bleomycin was more efficient in causing the resolution of oral leukoplakia than curcumin, and patients in group A were more satisfied. Curcumin was effective in non-homogenous leukoplakia with an appreciable resolution of dysplasia and VAS score reduction, even when the clinical lesion resolution was not substantial. Hence, bleomycin proved to be more effective than curcumin in treating oral leukoplakia by both subjective and objective means.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Saini A. Challenges of oral cancer in India. J Dent Res Prac 2021;3:1–2.  Back to cited text no. 1
    
2.
Borse V, Konwar AN, Buragohain P. Oral cancer diagnosis and perspectives in India. Sens Int 2020;1:100046.  Back to cited text no. 2
    
3.
Scheifele C, Reichart PA. Oral leukoplakia in manifest squamous epithelial carcinoma. A prospective clinical study of 101 patients. Mund Kiefer Gesichtschir 1998;2:326–30.  Back to cited text no. 3
    
4.
Fleskens S, Slootweg P. Grading systems in head and neck dysplasia: Their prognostic value, weaknesses and utility. Head Neck Oncol 2009;11:1–8.  Back to cited text no. 4
    
5.
Gnjatic S, Nagata Y, Jager E, Stockert E, Shankara S, Roberts BL, et al. Old LJ. strategy for monitoring T cell responses to NY-ESO-1 in patients with any HLA class I allele. Proc Natl Acad Sci U S A 2000;20:10917–22.  Back to cited text no. 5
    
6.
Chainani-Wu N. The safety and anti-inflammatory activity of curcumin is a turmeric component (Curcuma longa). J Altern Complement Med 2003;1:161–8.  Back to cited text no. 6
    
7.
Hammersley N, Ferguson MM, Rennie JS. Topical bleomycin in treating oral leukoplakia: A pilot study. Br J Oral Maxillofac Surg 1985;4:251–8.  Back to cited text no. 7
    
8.
Wong F, Epstein J, Millner A. Treatment of oral leukoplakia with topical bleomycin. A pilot study. Cancer 1989;15:361–5.  Back to cited text no. 8
    
9.
Malmström M, Hietanen J, Sane J, Sysmäläinen M. Topical treatment of oral leukoplakia with bleomycin. Br J Oral Maxillofac Surg 1988;6:491–8.  Back to cited text no. 9
    
10.
Epstein JB, Gorsky M, Wong FL, Millner A. Topical bleomycin for treating dysplastic oral leukoplakia. Cancer 1998;4:629–34.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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