Medical knowledge | Otorhinolaryngology, ear, nose, throat » Dr. Shamendra Kumar Meena - Recent Advancement in Otorhinolaryngology, Mitomycin C

Source: http://www.doksinet ISSN: 0976-0172 Journal of Bioscience And Technology www.jbstonlinecom Dr.SK Meena J Biosci Tech,Vol 7(3),2016,757-761 Recent Advancement in Otorhinolaryngology - Mitomycin-C Dr. Shamendra Kumar Meena Medical Officer (Clinical Tutor) E.NT Dept GMC Kota Rajasthan 324001, KR21, Civil line Nayapura Kota Rajasthan 324001 Abstract: Mitomycin-C is a chemotherapeutic drug that acts by inhibiting DNA synthesis. Its use and application in ENT has been increasing in recent years because of its mandatory effects on wound healing. Current applications include Tracheal Stenosis, nasal synechia, endoscopic dacryocystorhinostomy surgeries and allergic disease. This article reviews the current trends and uses of mitomycin-C in the eye and its related complications. 1. Introduction: Mitomycin-C (MMC) is an anti-neoplastic/ antibiotic agent isolated from soil bacterium Streptomyces caespitosus. It is used intravenously to treat upper gastro-intestinal tumors, anal

cancer, breast cancer and bladder tumors. Mitomycin C has also been used topically rather than intravenously in several areas like bladder cancers and intra-peritoneal tumors. It is now well known that a single instillation of this agent within 6 hours of bladder tumor resection can prevent recurrence. In esophageal and tracheal Stenosis application of MMC onto the mucosa immediately following dilatation will decrease restenosis by decreasing the production of fibroblasts and scar tissue. Its use and application in ENT has been increasing in recent years because of its modulatory effects on wound healing. 2. Pharmacology and mechanism of action: It is an anti-metabolite with anti-proliferative effect on cells showing the highest rate of mitosis by inhibiting DNA synthesis and interferes with RNA transcription and protein synthesis. DNA is inhibited by cross linking at the N position of Adenine and at 06 and N position of Guanine. The cell cycle is most affected during the late G-I and

early S-phase. The chemical formula is C15H18N4O5. Key Words: Mitomycin-C, ENT diseases, Synechia, Stenosis 3. Drug Reconstitution and Pharmacokinetics: The drug is available in a vial (2mg/ml). It is further reconstituted with normal saline (5ml) to make 0.4mg/ml or in 10ml to make 0.2mg/ml the drug should be stored under refrigeration after reconstitution to preserve its potency and under these conditions; it is potent for a period of two weeks only. MMC is delivered in solubilized form. 4. Clinical uses of Mitomycin C in Otorhinolaryngology: a) b) c) d) e) f) g) h) i) Nasal synechia Nasopharyngeal carcinoma Tracheal Stenosis 4-Keloids head and neck region After Myringotomy FESS in Chronic Rhino sinusitis Endoscopic DCR Pharygo-oesophageal stricture Vocal cord paralysis a) Nasal Synechia: Synechia is the most frequent complication after sinus surgery and has been reported in up to 36% of cases. Several types of materials have been used to reduce the incidence of synechia,

including Mitomycin C (MMC). 757 Source: http://www.doksinet Dr.SK Meena J Biosci Tech,Vol 7(3),2016,757-761 Postoperative synechia is the most frequently reported complication in the literature, found in between 11% and 36% of the cases. Revision surgery is required in 1% to 2% of the cases 3-6. When only revision surgery is considered, the incidence rate ascends to 56%2. A review on 182 FESS patients revealed that the only findings related to little clinical improvement were fibrosis in medial antrostomies and in the ethmoidal region1 Mitomycin C was not effective in preventing postoperative synechiae in patients submitted to functional endoscopic sinus surgery. Mitomycin C was effective in preventing postoperative total synechiae in patients submitted to functional endoscopic sinus surgery. Studies with larger populations, higher dosages, and longer time of exposure are required. b) Nasopharyngeal Carcinoma Mitomycin C (MMC) is a classic chemotherapeutics which exhibits

effective anti-tumour effects against a variety of solid tumours by inducing apoptosis and reducing drug resistance 7, 8. Notably, the inhibitory effects of MMC against NPC cells have been reported previously 9. Combination therapy with various drugs is a common strategy in cancer treatment to obtain an additive or synergistic effect and to reduce the potential toxicity. So far, numerous MMC-containing combinations. Remedies have been reported with encouraging clinical effects 10, 11. combined chemotherapy and antibody targeted therapy to show thatMMC and anti-LMP1 Fab combination exhibited synergistic effects to inhibit NPC tumor growth in vivo with high efficacy and much less toxicity associated with MMC. The anti-tumour effects appear to be mediated via the induction of apoptosis and the ISSN: 0976-0172 Journal of Bioscience And Technology www.jbstonlinecom inhibition of VEGF expression. This novelcombination therapy represents a promising strategy for the treatment of NPC. c)

Laryngeal Stenosis: The management of benign stenosis of the central airways continues to be challenging. Acquired benign airway stenosis can resultfrom a variety of injuries to the airway wall:ischemia related to endotracheal intubation,surgical procedures such as tracheotomy orairway resection, chemical or thermal injury,direct mechanical trauma after bacterial ormycobacterial infections, from inflammatorydiseases affecting the airways such as Wegener granulomatosis or sarcoidosis, after radiotherapy,stent-stimulated granulation tissue, andidiopathic when the cause cannot be identified.12After any of the afore-mentioned damagesto the mucosa, the following inflammatoryprocess activates fibroblasts to participate inwound healing. Fibroblasts synthesize several factors, such as transforming growth factor b1and basic fibroblast growth factor, that stimulatethe production of extracellular matrix components, leading to scar formation and contractionat the stenosis site.13,14 The same

mechanism takes place in restenosis.Current treatment includes surgical resectionas the first option. However, when surgery isunsuitable because of the patient’s clinical orrespiratory conditions or airway issues, endoscopicapproaches need to be considered.12 Airway patency can be reestablished by means ofmechanical dilation with the bevel of the rigidbronchoscope, balloon inflation, laser ablation,electrocautery or argon plasma coagulator, stentinsertion, or usually, a combination of any of theabove.12However, a high rate of restenosis rangingfrom 40% to 70% has been reported after theendoscopic treatment of tracheal stenosis,15–18 urging a need for therapies aimed to obtainbetter results. Treatments studied to reducerelapses include steroids, 5-fluorouracil, 758 Source: http://www.doksinet Dr.SK Meena J Biosci Tech,Vol 7(3),2016,757-761 halofuginone, tamoxifen, and mitomycin-C (MMC).18 ISSN: 0976-0172 Journal of Bioscience And Technology www.jbstonlinecom Mitomycin is an

antibiotic that was isolatedfrom the bacteria Streptomyces caespitosusin1956. Its C-form is an alkylating agent thatinhibits deoxyribonucleic acid synthesis. It was first used as an anticancer drug. It has also beenused in ophthalmologic procedures to reducecorneal scarring and recently in the treatment ofbenign airway stenosis.19 as these lesions can cause significant pain, pruritus (itching), and physical disfigurement 25,26 . Topical Mitomycin C application for keloids after surgical excision showed success rate of 95% without any toxic side effects or complications which is in line with previous study by C.E Stewart et al 20 Combination of surgical excision with topical mitomycin-C application is highly safe and effective in treating head and neck keloids in contrast to other modalities which have either a high recurrence rate or are invasive. d) Keloid: e) After Myringotomy: Keloids were described by Egyptian surgeons around 1700 BC21. Baron Jean-Louis Alibert (1768–1837)

identified the keloid as an entity in 1806. He called them cancroïde, later changing the name to chéloïde to avoid confusion with cancer. The word is derived from the Greek χηλή, chele, meaning "hoof", here in the sense of "crab pincers", and the suffix -oid, meaning "like". Persons of any age can develop a keloid. Children under 11 are less likely to develop keloids, even from ear piercing. We know that certain dark-skinned races are more prone to the development of keloids. For instance, the occurrence of keloids in black patients is between 4% and 16% 22. Keloids may also develop from Pseudofolliculitisbarbae. The tendency to form keloids is speculated to be hereditary. Keloids can tend to appear to grow over time without even piercing the skin, almost acting out a slow tumorous growth; the reason for this is unknown. The ratio of type I collagen to type III collagen is elevated 22.Histologically, keloids are fibrotic tumors characterized by a

collection of atypical fibroblasts with excessive deposition of extracellular matrix components, especially collagen, fibronectin, elastin, and proteoglycans 23,24. Generally, they contain relatively acellular centers and thick, abundant collagen bundles that form nodules in the deep dermal portion of the lesion. Keloids present a therapeutic challenge that must be addressed, Mitomycin C (MMC) is an antineoplastic agent of the antibiotic subgroup, which is produced by a fungus called Streptomyces caespitosus. It blocks DNA and RNA replication by interfering in the G1 and S phases at the late stages of the cell cycle. Local application of MMC to the margins of perforations after myringotomy is reported to delay perforation closure 27,28 The aim of this study was to investigate the effects of locally applied MMC on the duration of TM healing and on the expression of bFGF, TGF-β1, and KGF-1 after perforations induced by myringotomy. f) FESS In Chronic Rhinosinusitis: Mitomycin-C (MMC):

MMC is an alkylating antineoplastic antibiotic that prevents replication of fibroblasts and epithelial cells, in otolaryngology MMC is currently under inquiry for the prevention of laryngotracheal stenosis, as an adjunct to FESS to prevent closure of the maxillarysinus antrostomy.29 MMC operates by disrupting base paring of DNA molecules in the G-1 phase of cell cycle, and inhibits formation of RNA and protein synthesis- this way inhibits proliferation of fibroblasts. Additional function is inhibition of apoptosis in fibroblasts and blockage of 759 Source: http://www.doksinet Dr.SK Meena J Biosci Tech,Vol 7(3),2016,757-761 angiogenesis. Topical applications of MMC over last decade extended to fields of plastic surgery and rhinology especially endoscopic sinus surgery (ESS) and acryocystorhinostomy (DCR).30, 31 The concentration of MMC ranged from to 1.5 ml 03 mg/ml to 06 mg/ml, whereas dose applied ranged from 0.5 ml and duration of topical MMC application was 5 minutes in majority

(7 out of 9) of studies, 4 minutes in 2 studies. Application method was in the way of soaked cotton pledgets 5 in 9 studies, ribbon gauze in 2 studies and Merocel pack in 1 study. No studies report any adverse effects or systemic toxicity of topical MMC applied for 5 minutes and in maximum concentrations-0.6 mg/ ml and maximum dose of 1.5 ml Years of experiences from ophthalmologists shown that MMC in concentration of 0.4 mg/ml for 5 minutes appears to be very safe. The aim of the study was to determine whether topical application of Mitomycin-C at the conclusion of FESS decreases the incidence of postoperative adhesion formation. g) Endoscopic Dacryocystorhinostomy The most important cause of failure of DCR surgery is fibrosis occurring under the flaps near the osteotomy sites. MMC inthese cases tends to suppress fibrous proliferationand scar formation. Intra-operative MMC application is effective in increasing the success rate of DCR surgery and no significant complications resulted

from its use 32. The non-patency rate in the MMC group is 4.5% compared to 114% in the conventional group. A piece of cotton soaked with 02mg/ml MMC is applied to the osteotomy site for 30 minutes intra-operatively is effective in maintaining a larger osteotomy size and also improves success rates over the traditional DCR procedure 33. ISSN: 0976-0172 Journal of Bioscience And Technology www.jbstonlinecom Dose: 0.02 to 004% for 5-30 minutes h).Pharyngoesophageal stricture To assess the role of mitomycin C (MMC) in the management of Pharyngoesophageal stricture after total laryngopharyngectomy and free flap reconstruction. Five patients since 1998 underwent evaluation and treatment for pharyngoesophageal stricture after totallaryngopharyngectomy and free flap reconstruction. The method of reconstruction included four tubedradial forearm free flaps and one jejunal free flap.(Laryngoscope 2003 Sep;113(9):1499-502 Donald J Annino, Laura A Goguen) 5. Conclusion: The use of topical

Mitomycin C in Otorhinolaryngology it is increasing in every subspecialty but risk benefit ratio should be considered, keeping in mind its complications. The dose and duration of application of MMC depends on surgery in which it is being used but is still controversial. Trials with longer follow up are required to establish safety and efficacy of drug. 6. References: [1]. Chambers DW, Davis WE, Cook PR, Nishioka GJ, Rudman DT. Long-term outcome analysis of functional endoscopic sinus surgery: correlation of symptoms with endoscopic examination findings and potential prognostic variables. Laryngoscope 1997;107(4):504-10. [2]. Ramadan HH Surgical causes of failure in endoscopic sinus surgery. Laryngoscope. 1999;109(1):27-9. [3]. White A, Murray JA Intranasal adhesion formation following surgery for chronic nasal obstruction. Clin Otolaryngol Allied Sci. 1988;13(2):139-43 [4]. Shone GR, Clegg RT Nasal adhesions J Laryngol Otol. 1987;101(6):555-7 [5]. May M, Levine HL, Mester SJ, Schaitkin

B Complications of endoscopic sinus surgery: analysis of 2108 patientsincidence and prevention. Laryngoscope. 1994;104(9):1080-3 760 Source: http://www.doksinet Dr.SK Meena J Biosci Tech,Vol 7(3),2016,757-761 [6]. Vleming M, Middelweerd RJ, de Vries N Complications of endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg. 1992;118(6):617-23 [7]. Volpato, M; Seargent, J; Loadman, PM; Phillips, R.M Formation of DNA interstrandcross-links as a marker of Mitomycin C bioreductive activation and chemosensitivity. Eur JCancer 2005, 41, 1331– 1338. [8]. Cao, Y; Chen, D; Zhao, P; Liu, L; Huang, X; Qi, C.; Liu, Y; He, H; Wang, Q; Liu, Y;Chen, S Intracellular delivery of mitomycin C with targeted polysaccharide conjugates against multidrug resistance. Ann Biomed Eng 2011, 39, 2456–2465 [9]. Ming, H; Zhang, D; Lin, H; Chen, R; Feng, Z; Zhu, J. Inhibiting effect of mitomycin C onhuman nasopharyngeal carcinoma cell line HNE2, HNE2/lmp1 and its mechanism. J Clin MedPrac 2009, 13, 21–32.

[10]. Li, M; Zhang, J; Wang, D; Zhong, B; Tucker, S; Lu, C.; Cheng, J; Cao, C; Xu, J; Xu, J;Pan, H A phase II study of intra-arterial chemotherapy of 5fluorouracil, cisplatin, and mitomycinC for advanced nonresectable gastric cancer.Anticancer 2009, 20, 941–945. [11]. Xu, Y; Kolesar, JM; Schaaf, LJ; Drengler, R; Duan, W.; Otterson, G; Shapiro, C; Kuhn, J.;Villalona-Calero, M.A Phase I and pharmacokinetic study of mitomycin C and celecoxib aspotential modulators of tumorresistance to irinotecan in patients with solid malignancies. CancerChemother.Pharmacol2009, 63, 1073–1082 [12]. Ernst A, Feller-Kopman D, Becker HD, et al Centralairway obstruction. Am J RespirCrit Care Med.2004;169:1278–1297 [13]. Karagiannidis C, Velehorschi V, Obertrifter B, et al.High-level expression of matrix-associated transforminggrowth factor-X1 in benign airway stenosis. Chest2006;129:1298–1304 [14]. Chen T, Kunnavatana SS, Koch RJ Effects ofmitomycin-C on normal dermal

fibroblasts.Laryngoscope2006;116:514–517 [15]. Simpson GT, Strong MS, Healy GB, et al Predictive factors of success or failure in the endoscopic management of laryngeal and tracheal stenosis. Ann Otol Rhinol Laryngol. 1982;91:384–388 [16]. Duncavage JA, Ossoff RH, Toohill RJ Carbon dioxide laser management of laryngeal stenosis. Ann Otol Rhinol Laryngol. 1985;94:565–569 [17]. Ossoff RH, Tucker GF Jr, Duncavage JA, et al Efficacy of bronchoscopic carbon dioxide laser surgery for benign strictures of the trachea. Laryngoscope. 1985;95:1220–1223 [18]. Smith ME, Elstad M Mitomycin C and the endoscopictreatment of laryngotracheal stenosis: are two applicationsbetter than one? aryngoscope. 2009;119:272–283. [19]. Beretta G Mitomycin C: Fifty Years’ Medical Experience.Turin: Edizioni Minerva Medica; 2005 [20]. [21]. [22]. [23]. [24]. [25]. [26]. [27]. [28]. [29]. [30]. [31]. [32]. [33]. ISSN: 0976-0172 Journal of Bioscience And Technology www.jbstonlinecom Stewart CE

4th, Kim JY, Application of mitomycin-C for head and neck keloids, otorhinolaryngology-head and neck surgery, 2006 Dec;135(6):946-50. Gupta M, Narang T.J Role of mitomycin C in reducing keloid recurrence: patient series and literature review. Laryngol Otol 2011 Mar; 125(3):297-300. Stucker FJ, Ed Hoasjoe, DK Ed Aarstad, R Fed, Current Therapy In Otolaryngology–Head and Neck Surgery. 5th St Louis, Mo Mosby-Yearbook Inc1994;113- 118 Stucker FJ, Goco PE.The treatment of hypertrophic scars and keloids. Facial PlastSurgClin North Am 1998;6191- 194 Bailey JN, Waite AE, Clayton WJ, Rustin MH. Br J Dermatol, Application of topical mitomycin C to the base of shave-removed keloid scars to prevent their recurrence. 2007 Apr; 156(4):682-6 Epub 2007 Jan 30 Stewart CE 4th, Kim JY, Application of mitomycin-C for head and neck keloids. Otolaryngol Head Neck Surg. 2006 Dec;135(6):946-50 Seo SH, Sung HW.J EurAcadDermatolVenereol, Treatment of keloids and hypertrophic scars using topical and

intralesionalmitomycin C. 2012 May; 26(5):634-8. doi:101111/j1468-3083201104140x Epub 2011 Jun 9 O’ Reill RC, Steven A, Goldman SA, Widner S, Cass SP. Creating a stable tympanic membrane perforation using mitomycin C. Otolaryngol Head Neck Surg 2001; 124: 40-5. Kang SG, Chung H, Yoo YD, Lee JG, Choi YI , Yu YS. Mechanism of growth inhibitory effect of Mitomycin-C on cultured human retinal pigment epithelial cells: apoptosis and cell cycle arrest. Curr Eye Res 2001; 22: 174-81 Ahmed Hesham, Ahmed Fathi et al; ”Laser and topical mitomycin C for management of nasal synechiae after FESS: a preliminary report”; Eur Arch Otorhinolaryngol. 2011 Mar 30 Egbert J D,Veen, Fredrik G. Dikkers;”Topical use of MMC in the upper aerodigestive tract: a review on the side effects”; Eur Arch Otolaryngology (2010) 267: 327-334. Peter D. Karkos, Leong SC, Sastry A, Assimakopoulos AD, Swift AC; ”Evidence-based applications of mitomycin C in the nose” American Journal of Otolaryngology-Head and

Neck Medicine and Surgery; Sep 2010. S. Liao, S KaoJ Tseng, M Chen, and P Hou, Results of intraoperative mitomycin C application in dacryocystorhinostomy Br J Ophthalmol. 2000 August; 84(8): 903–906. Kao SC, Liao CL, Tseng JH, Chen MS, Hou PK. Dacryocystorhinostomy with intraoperative mitomycin C. Ophthalmology 1997;104:86-91 761