https://doi.org/10.5812/ijcm.7900

Bleomycin Chemotherapy for Oral Leukoplakia

authors:

avatar Shishir Ram Shetty 1 , * , avatar Sura Ali Ahmed Foud Al- Bayati 2 , avatar Ahmed Atef Shon 3

Assistant Professor, Department of Oral Medicine and Radiology, College of Dentistry, Gulf Medical University, Ajman, United Arab Emirates
Associate Dean and Head of the Department of Oral Medicine and Radiology, College of Dentistry, Gulf Medical University, Ajman, United Arab Emirates
Assistant Professor in Prosthodontics, College of Dentistry, Gulf Medical University, Ajman, United Arab Emirates
International Journal of Cancer Management: Vol.10, issue 11; e7900
published online: November 27, 2017
article type: Discussion
received: July 17, 2016
revised: October 3, 2016
accepted: October 30, 2017

How To Cite Ram Shetty S, Ali Ahmed Foud Al- Bayati S, Atef Shon A. Bleomycin Chemotherapy for Oral Leukoplakia. Int J Cancer Manag. 2017;10(11):e7900. https://doi.org/10.5812/ijcm.7900.

1. Introduction

Over the years potentially malignant disorders like oral leukoplakia (OL) and oral erythroplakia (OE) are associated with dysplastic cellular changes and hence carry a risk of undergoing malignant transformation leading to oral cancer (OC) (1). Numerous surgical and nonsurgical modalities have been used for treatment of OL (2). Some of the non-surgical modalities used for the treatment of OL include photodynamic therapy, beta-carotene, lycopene, or vitamin A (2, 3). Bleomycin a chemotherapeutic agent has also been used for treatment of leukoplakia and other malignant lesions (4-8). Apart from topical application report intralesional injection of bleomycin into OL lesion has been performed with good results (9). Another study suggested the delivery of bleomycin into head and neck tumors using iontophoresis (10). The purpose of this article is to provide a brief review of the use of bleomycin in the treatment of oral cancer and precancerous lesion (Table 1).

2. Biological Properties of Bleomycin

The bleomycin is glycopeptide-derived antibiotic isolated from streptomyces (11). The biological action of bleomycin is through a sequence-selective, metal-dependent oxidative cleavage of DNA and RNA in the presence of oxygen. It can mediate the oxidative degradation of all major classes of cellular RNAs and inhibition of DNA synthesis (11).

Table 1.

Displaying Studies Conducted by Researchers Using Bleomycin in Oral Cancer and Precancer Patients

Researchers and YearStudy SubjectsDrug AdministrationResults
Hammersley N et al. 19856 oral leukoplakia subjects0.5% bleomycin topical applicationSignificant reduction in clinical size and dysplastic features
Malmstrom M et al. 198810 oral leukoplakia subjectsTopical bleomycinEpithelial dysplasia resolved in 5 out 10 study subjects
Tashiro H et al. 198811 oral cancer patientsTopical bleomycin and radiotherapyOne subject had early recurrence and three had recurrences after 2 years
Wong F et al. 198912 (2 subjects were exclude from analysis)0.5% topical bleomycinSubjects treated with 0.5% bleomycin showed decrease in the clinically observed thickness
1% topical bleomycinSubjects treated with 1% bleomycin showed complete resolution of lesion
Epstein JB et al. 199422 oral leukoplakia subjects1% topical bleomycinSignificant reduction in clinical size of the lesion and reduction in dysplasia
Epstein JB et al. 199819 oral leukoplakia subjects1% topical bleomycin75% of study subjects showed resolution of dysplasia in follow-up biopsy

3. Bleomycin in Dermatology

Studies have suggested intralesional injection of bleomycin to be highly effective in treatment of warts (12). Off-label use of intralesional bleomycin is another primary and/or adjunctive therapy for different cutaneous lesions dermatology as several types of cutaneous malignancies, telangiectasias, vascular malformations, hemangiomas, and lesions of leishmaniasis cutisand condyloma acuminate (13). Studies have also suggested intralesional bleomycin to be more effective in treatment of warts when compared to surgical modalities like cryotherapy (14). Recent research has revealed that bleomycin is a reliable and safe treatment modality for warts resistant to other therapeutics (15).

4. Bleomycin in Cancer Treatment

Bleomycin along with Adriamycin, vinblastine and dacarbazine is the standard chemotherapy regimen for Hodgkin’s, and non-Hodgkin’s lymphoma disease squamous cell cancers, sarcoma, melanoma, and testicular cancer. Also it is used to treat malignant pleural effusion and Leukemias (16). Bleomycin is found to concentrate more in lymphoid tissue and does not cause excessive myelo-suppression, thus is the preferred agent in chemotherapeutic regimens for non hodgkins lymphoma also (17). Bleomycin is one of the important drugs in induction chemotherapy for testicular cancer (18). Bleomycin also is a key component in the chemotherapy regimens for cervical and ovarian cancer (19, 20).

5. Bleomycin in Oral Leukoplakia

Oral leukoplakia is defined as “a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion. It is the most common potentially malignant disorder”. A risk factor for malignant transformation of OL is Candida invasion. It may be associated with certain clinical characteristics such as lesion type, size, and site, dysplasia, and tobacco use. The prevalence of OL is approximately 2% with an annual malignant transformation of approximately 1% (21).

Warnakulasuriya et al. listed the overall risk factors for malignant transformation in leukoplakia as follows: female gender, long duration of leukoplakia, leukoplakia in nonsmokers (idiopathic leukoplakia), location on the tongue and/or floor of the mouth, nonhomogeneous type, presence of Candida albicans and presence of epithelial dysplasia (21).

One of the earliest reported studies using bleomycin was carried out by Hammersley N et al. wherein a 0.5 per cent (w/v) solution of bleomycin sulphate in dimethyl sulphoxide was used for 12 to 15 days on six subjects (8). Significant clinical and histopathological improvements were observed. After their study, using bleomycin Malmstrom M et al. stated that clinically visible changes can be appreciated only three months after the application of bleomycin therapy but once the lesions disappear, the recurrence rate is less than the cases which have been treated surgically (7). Tashiro H et al. used non-surgical technique combining topical application of bleomycin and radiotherapy for oral cancer cases (22). They concluded that the apparent cure brought about by this conservative modality may harbor latent evidence of malignancy (22).Wong F and his colleagues from their study using bleomycin on oral leukoplakia observed that when 0.5% of topical bleomycin was used, it caused reduction in clinically observed thickness of oral leukoplakia lesions (23). However, they observed that when 1% topical bleomycin was used, complete resolution of the lesion was observed (23). Epstein JB and his fellow researchers observed reduced histopathological evidence of dysplasia in 75% of study subjects with oral leukoplakia (24).

Besides studies, few case reports have been also published wherein bleomycin has been used to successfully manage oral carcinoma (25, 26). Recent studies by Strojan P and his associates revealed that a combination of radiotherapy and chemotherapy (Vinblastine, Methotrexate, and Bleomycin) was a very good alternative in inoperable verrucous carcinoma of the head and neck region (27). The research trends suggest that the recent studies are more focused on using combination therapies involving bleomyicin rather than single drug regimens.

6. Bleomycin Toxicity

The major toxic effect of bleomycin is on the pulmonary system (28). Bleomycin induced pneumonitis occurs in nearly 20% of cancer patients who are administered regimens containing bleomycin (29). With predisposing factors like pulmonary a disorders renal disorders and old bleomycin toxicity can be fatal (30, 31). However several cases have been reported wherein the toxicity has been reversed by administering high dose of steroids (32).

To conclude, in this article we have made an attempt to briefly present the therapeutic actions of bleomycin with special emphasis on the management of oral cancer and pre-cancer with bleomycin. The research trend in this field shows a combination therapy involving modality life radiotherapy show more promise in treatment of cancer rather than single drug therapy.

References

  • 1.

    Epstein JB, Wong FL, Millner A, Le ND. Topical bleomycin treatment of oral leukoplakia: a randomized double-blind clinical trial. Head Neck. 1994;16(6):539-44. [PubMed ID: 7529754].

  • 2.

    Ribeiro AS, Salles PR, da Silva TA, Mesquita RA. A review of the nonsurgical treatment of oral leukoplakia. Int J Dent. 2010;2010:186018. [PubMed ID: 20339486]. https://doi.org/10.1155/2010/186018.

  • 3.

    Saito T, Sugiura C, Hirai A, Notani K, Totsuka Y, Shindoh M, et al. Development of squamous cell carcinoma from pre-existent oral leukoplakia: with respect to treatment modality. Int J Oral Maxillofac Surg. 2001;30(1):49-53. [PubMed ID: 11289621].

  • 4.

    Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral leukoplakia. Cochrane Database Syst Rev. 2006;(4). CD001829. [PubMed ID: 17054142]. https://doi.org/10.1002/14651858.CD001829.pub3.

  • 5.

    Lele S. Although leukoplakia responds to some treatments relapses and adverse effects are common. Evid Based Dent. 2005;6(1):15-6. [PubMed ID: 15789045]. https://doi.org/10.1038/sj.ebd.6400311.

  • 6.

    de Vries N, van Zandwijk N, Pastorino U. Chemoprevention of head and neck and lung (pre)cancer. Recent Results Cancer Res. 1999;151:13-25. [PubMed ID: 10337716].

  • 7.

    Malmstrom M, Hietanen J, Sane J, Sysmalainen M. Topical treatment of oral leukoplakia with bleomycin. Br J Oral Maxillofac Surg. 1988;26(6):491-8. [PubMed ID: 2462447].

  • 8.

    Hammersley N, Ferguson MM, Rennie JS. Topical bleomycin in the treatment of oral leukoplakia: a pilot study. Br J Oral Maxillofac Surg. 1985;23(4):251-8. [PubMed ID: 2412577].

  • 9.

    Hisano Y, Satoh T, Suzuki M, Kanai Y. [An effective case of local injection therapy of oral leukoplakia with bleomycin (author's transl)]. Shigaku. 1978;66(1):125-8. [PubMed ID: 94664].

  • 10.

    Hayasaki K, Kitamura T, Kaneko T, Tachibana M, Kobayashi N, Tosaka K, et al. [Application of BLM-iontophoresis for the tumor-therapy of the head and neck area (author's transl)]. Nihon Gan Chiryo Gakkai Shi. 1977;12(4):522-7. [PubMed ID: 75935].

  • 11.

    Galm U, Hager MH, Van Lanen SG, Ju J, Thorson JS, Shen B. Antitumor antibiotics: bleomycin, enediynes, and mitomycin. Chem Rev. 2005;105(2):739-58. [PubMed ID: 15700963]. https://doi.org/10.1021/cr030117g.

  • 12.

    Soni P, Khandelwal K, Aara N, Ghiya BC, Mehta RD, Bumb RA. Efficacy of Intralesional Bleomycin in Palmo-plantar and Periungual Warts. J Cutan Aesthet Surg. 2011;4(3):188-91. [PubMed ID: 22279384]. https://doi.org/10.4103/0974-2077.91250.

  • 13.

    Saitta P, Krishnamurthy K, Brown LH. Bleomycin in dermatology: a review of intralesional applications. Dermatol Surg. 2008;34(10):1299-313.

  • 14.

    Dhar SB, Rashid MM, Islam A, Bhuiyan M. Intralesional bleomycin in the treatment of cutaneous warts: a randomized clinical trial comparing it with cryotherapy. Indian J Dermatol Venereol Leprol. 2009;75(3):262-7. [PubMed ID: 19439878]. https://doi.org/10.4103/0378-6323.48428.

  • 15.

    Aziz-Jalali MH, Ghafarpour G, Rezaei MR, Behzadi AH, Nasab MR, Nilforoushzadeh MA. Efficacy of intralesional bleomycin in the treatment of resistant warts. J Skin Stem Cell. 2014;1(1):1887.

  • 16.

    Canellos GP, Duggan D, Johnson J, Niedzwiecki D. How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol. 2004;22(8):1532-3. [PubMed ID: 15084636]. https://doi.org/10.1200/JCO.2004.99.010.

  • 17.

    Bayer RA, Gaynor ER, Fisher RI. Bleomycin in non-Hodgkin's lymphoma. Semin Oncol. 1992;19(2 Suppl 5):46-52. discussion 52-3. [PubMed ID: 1384144].

  • 18.

    Kawai K, Akaza H. Bleomycin-induced pulmonary toxicity in chemotherapy for testicular cancer. Expert Opin Drug Saf. 2003;2(6):587-96. [PubMed ID: 14585067].

  • 19.

    Pautier P, Gutierrez-Bonnaire M, Rey A, Sillet-Bach I, Chevreau C, Kerbrat P, et al. Combination of bleomycin, etoposide, and cisplatin for the treatment of advanced ovarian granulosa cell tumors. Int J Gynecol Cancer. 2008;18(3):446-52. [PubMed ID: 18494093].

  • 20.

    Tobias J, Buxton EJ, Blackledge G, Mould JJ, Monaghan J, Spooner D, et al. Neoadjuvant bleomycin, ifosfamide and cisplatin in cervical cancer. Cancer Chemother Pharmacol. 1990;26 Suppl:S59-62. [PubMed ID: 1693316].

  • 21.

    Kayalvizhi EB, Lakshman VL, Sitra G, Yoga S, Kanmani YR, Megalai N. Oral leukoplakia: A review and its update. J Med Radiol Pathol Surg. 2016;2:18-22.

  • 22.

    Tashiro H, Ozeki S, Higuchi Y, Okamoto M. Late occurring recurrence of oral cancer after combined treatment with bleomycin and radiotherapy. Cancer. 1988;61(12):2418-22. [PubMed ID: 2452683].

  • 23.

    Wong F, Epstein J, Millner A. Treatment of oral leukoplakia with topical bleomycin. A pilot study. Cancer. 1989;64(2):361-5. [PubMed ID: 2472197].

  • 24.

    Epstein JB, Gorsky M, Wong FL, Millner A. Topical bleomycin for the treatment of dysplastic oral leukoplakia. Cancer. 1998;83(4):629-34. [PubMed ID: 9708924].

  • 25.

    Tsuji T. Bleomycin iontophoretic therapy for verrucous carcinoma. Arch Dermatol. 1991;127(7):973-5. [PubMed ID: 1712184].

  • 26.

    Kapstad B, Bang G. Verrucous carcinoma of the oral cavity treated with bleomycin. Oral Surg Oral Med Oral Pathol. 1976;42(5):588-90. [PubMed ID: 62332].

  • 27.

    Strojan P, Soba E, Budihna M, Auersperg M. Radiochemotherapy with Vinblastine, Methotrexate, and Bleomycin in the treatment of verrucous carcinoma of the head and neck. J Surg Oncol. 2005;92(4):278-83. [PubMed ID: 16299796]. https://doi.org/10.1002/jso.20422.

  • 28.

    Patil N, Paulose RM, Udupa KS, Ramakrishna N, Ahmed T. Pulmonary Toxicity of Bleomycin - A Case Series from a Tertiary Care Center in Southern India. J Clin Diagn Res. 2016;10(4):FR01-3. [PubMed ID: 27190828]. https://doi.org/10.7860/JCDR/2016/18773.7626.

  • 29.

    Carnevale-Schianca F, Gallo S, Rota-Scalabrini D, Sangiolo D, Fizzotti M, Caravelli D, et al. Complete resolution of life-threatening bleomycin-induced pneumonitis after treatment with imatinib mesylate in a patient with Hodgkin's lymphoma: hope for severe chemotherapy-induced toxicity? J Clin Oncol. 2011;29(24):691-3. [PubMed ID: 21709191]. https://doi.org/10.1200/JCO.2011.35.6733.

  • 30.

    Debnath J, Singh HP, George RA, Satija L, Chawla N, Sarma YS, et al. Reversible Bleomycin Toxicity. Med J Armed Forces India. 2010;66(3):290-1. [PubMed ID: 27408324]. https://doi.org/10.1016/S0377-1237(10)80071-1.

  • 31.

    Keijzer A, Kuenen B. Fatal pulmonary toxicity in testis cancer with bleomycin-containing chemotherapy. J Clin Oncol. 2007;25(23):3543-4. [PubMed ID: 17687159]. https://doi.org/10.1200/JCO.2007.12.2218.

  • 32.

    Maher J, Daly PA. Severe bleomycin lung toxicity: reversal with high dose corticosteroids. Thorax. 1993;48(1):92-4. [PubMed ID: 7679525].