Usefulness and safetyOf Cryotherapy versus Bleomycin injection in the treatment of localised keloids.
- Conditions
- Hypertrophic scar,
- Registration Number
- CTRI/2020/08/027352
- Lead Sponsor
- Bankura Sammilani Medical College
- Brief Summary
**THESISTOPIC:** Evaluation of Efficacy, Tolerability and safety,of Cryotherapy versus Intralesional bleomycin injection in the treatmentof localised keloids: An institution based open labelled randomised controlledtrial.
**OBJECTIVEOF RESEARCH**
**Primary objective**: To assess effectiveness of Cryotherapy versus Intralesional Bleomycininjection in reducing the thickness of localised keloid.
**Secondary objective**:
a. To assess the effectiveness of these two different methods in decreasingpain and itching associated with keloid.
b. To assess tolerability and safety of the above-mentioned methods.
c. To assess the improvement in quality of life with these above-mentionedmethods.
**BACKGROUNDOF RESEARCH:**
**A) RATIONALE OF STUDY:** Keloids representa form of abnormal wound healing characterised by local fibroblast proliferation and excessivecollagen production in response to cutaneous injury.[3]For as longas physicians and surgeons have intervened in attempts to influence and improvekeloids inability of any therapeutictechnique to achieve satisfactory scar reductions in all patients has beenuncomfortably apparent.[4,5,6]Numerous treatment options areavailable, although the quality of evidence for their efficacy is generallylow, which should serve as an indication of the lack of consistency and predictability in outcomes among varioustreatment modalities.[7]
Numerous treatment methods, includingcryotherapy, intralesional injections, laser treatment, pressure therapy,radiation and topical treatment have been proposed for keloids.[8]Deepfreezing of the keloids leads to necrosis, crusting and eventually diminutionof the lesion.[3]Intralesional bleomycin is a relatively newer and 2ndor 3rd line therapy in treatment of keloids. Bleomycin induced apoptosiswith sclerosing action on endothelial cells inhibits collagen synthesis byinhibiting the lysyl-oxidase enzyme and TGF-BETA.[9] Thus the study evaluatesthe effectiveness, safety and patient friendliness (quality of life) ofCryotherapy versus Intralesional Bleomycin injection in treatment of localisedkeloid.
**B) INTRODUCTION:**
Keloids representan excessive connective tissue response to injury, which may be trivial. Akeloid is a benign well-demarcated overgrowth of fibrotic tissue which extendsbeyond the original boundaries of a defect. They appear to be unique to humansand the lack of an animal model has hampered studies into their pathogenesis. Ascar at any site has the potential to become keloidal although the earlobes,chin, neck, shoulders, upper trunk and lower legs are especially vulnerable.Lesions may follow trivial trauma or inflammatory conditions such as acne. Evenchemical trauma, from irritable herbal remedies can trigger keloid formation.Sometimes keloid appears to develop spontaneously, particularly on the upperchest. Introduction of foreign material, either exogenous such as suturematerial, or endogenous, such as embedded hairs, is another risk factor.Regression of keloids is a much slower process and keloids can expand graduallyover years.[1]
Patientswith keloid typically presents with pruritus, pain, ulceration, secondaryinfection, restricted motion and psychological disturbance due to cosmeticdisfigurement.[10] Given their intractable nature and highrecurrence rate, keloids are a great burden to the patients, physicians,scientists and society and are associated with physical aesthetic and social complaints.[11,12]
Numerous treatmentmethods, including cryotherapy, intralesional injections, laser treatment,pressure therapy, radiation and topical treatment have been proposed forkeloids. [7]
Cryotherapy has been widely used foryears and is regarded as an effective modality for treatment of keloids;several techniques and devices related to cryotherapy have been developed inthe clinical practice.[13,14]External cryotherapy, contact cryotherapywith spray technique, is an efficientand effective method for clinical use and has been performed over past fewyears; however numerous side effects such as oedema, swelling, blisterformation, oozing, depigmentation are inevitably encountered during the woundhealing process.[15] Also infrastructural problems like procurementof cryogen, storage and application within a stipulated time are some major demerits of cryotherapy.
Bleomycinis a cytotoxic antibiotic which induces apoptosis with sclerosing action onendothelial cells and inhibits collagen synthesis by inhibiting thelysyl-oxidase enzyme and TGF-BETA.[9] Bleomycin is available as apowder and should be reconstituted with sterile saline to the desiredconcentration. It is cheap, easy to administer, show high regression rates andhas minimum complications and recurrences shown by some clinical trials. Indermatology intralesional bleomycin has largely been used in the treatment ofrecalcitrant viral warts.[16] It has relatively low toxicity. Flu likesymptoms have been reported after intralesional use but significant systemictoxicity is rare. Local side effects of pain and swelling are common withintralesional use.[16]
**C)REVIEW OFLITERATURE**
Keloid scars have afflicted humans for many centuries, described as farback as 3000 BC in the Edwin Smith papyrus.[17] Keloids areproliferative scars, defined as benign mesenchymal tumours that extend beyondthe wound margin, that do not regress spontaneously and tend to recur followingexcision.[18,19] They are characterized by extensiveintradermal collagen and glycosaminoglycan deposition.[20,21]
Keloids are a common manifestation following abnormal wound healing,with an incidence of 5% to 16% in high-risk populations, which includesAfricans, Asians and Hispanics. [21,22] Although benign, keloidlesions can cause pain, paraesthesia and pruritus, as well as functional andaesthetic impairment. Consequently, patients may be burdened with markedphysical and psychosocial sequelae.[23]
Many studies have examined the pathophysiology of keloid scarring at thecellular level, but at present the exact underlying mechanisms are yet to becomprehensively understood. Many factors such as wound tension, skinpigmentation, genetic predisposition, immunoregulation and skin injury havebeen implicated in the etiology of keloidogenesis.[21,24,25]
With little known regarding the exact pathophysiological eventsunderlying this condition, the management of a keloid scar is clinicallychallenging. Many treatments have been advocated either alone or incombination, including surgical excision, intralesional chemotherapeuticinjection, radiotherapy, laser therapy, cryotherapy, topical silicone, systemicchemotherapy and pressure therapy, most of which have had varying and transientsuccess.[26,27,28] In addition, adverse effects from thedifferent treatments may significantly limit any benefits.[29]
**Rusciani *etal***. [30]1993 observed complete flattening in 73% cases in their study of treatment of keloids using cryotherapy.Side effects were limited to hypopigmentationand slight to moderate atrophy in some cases.
In a studyby **Zouboulis et al** [31] in 1993, 93 patientswith keloid and hypertrophic scars were treated using cryosurgery withoutinjection. Excellent recovery, good recovery, and treatment failure were32.35%, 29%, and 9.75%, respectively.
Indian studyconducted to assess the result of cryotherapy in small keloids by **Sharma *et* *a*l** [32]
2007 found excellent response in 43.3%patients, good result in 26.7% patients, fair and poor result in 16.7% and13.3%, respectively. A better result in this study could be due to the factthat they included only small lesions with depth less than 0.5 cm and gavefreeze-thaw cycle of 30 seconds each
**Bodokh and Brun** 1996[33]were the first to report the use of bleomycin for scar therapy. They treated 31keloids and 5 hypertrophic scars with 3 to 5 intralesional infiltrations ofbleomycin within a 1-month period. Total regression was obtained in 84% ofscars.
In anotherstudy, **Espana *et al.***2001[34] injected1.5 U/mL bleomycin into keloid and hypertrophic scars of 13 patients using amultiple needle puncture approach. Patients received between 1-5 treatments;each session held 1-4 months apart. All patients were relieved of pruritusafter the first session. Complete flattening of the scar was achieved in 53.8%of patients and in the other 46.2% of patients there was a >75% resolutionin scar thickness. At 12 months follow up, there was a 15.4% recurrence rate.
Using a differentapproach, **Saray and Gulec** 2005[28] administered monthlyintralesional bleomycin (1.5 U/mL) into 15 keloid and hypertrophic scars usinga jet injector. Here, 73.3% of scars became completely flat and in the other26.7% there was >50% reduction in thickness. During the mean follow upperiod of 19 months, there were no reported recurrences.
More recently, **Naeini *etal***.2006[20] compared the efficacy of bleomycin tattoomonotherapy with that of cryotherapy combined with intralesional triamcinolone(TAC) injection. In the cryotherapy combined with TAC group, lesions less than100 mm2 showed a significantly better response than largerlesions (P=0.007), whereas in the bleomycin group, the size of lesion did notaffect the rate of resolution. There was no statistical difference between thetwo groups in lesions less than 100 mm2. However, in larger lesions,the therapeutic response to bleomycin was significantly better.
In a study of keloids and hypertrophic scars with intralesionalbleomycin in skin of colour by **Payapvipapong K *et al****.* 2015 [35]Twenty-six patients with keloids or hypertrophic scars were recruited. Theclinical improvement as assessed by the POSAS was not statisticallysignificant. In terms of patients satisfaction score, one half of both groupsreported a very good improvement. Photographic as well as ultrasonographicevaluation showed no difference between the two groups. Bleomycin was found toenter the blood circulation in a very small amount. There was no skin atrophydetected in this study. They concluded that Intralesional bleomycin is a safeand effective treatment for keloids and hypertrophic scars. The treatment iscomparable to intralesional triamcinolone. Unfortunately, hyperpigmentation wasthe major side effect in darker skin type.
In a study by **Aggarwal H *et al****.* 2015 [36] they included 50 patients with keloids andhypertrophic scars. Bleomycin was administered through multiple superficialpuncture technique. Three applications were given at intervals of 15 days each,followed by a fourth and final application 2 months after the last application.Final results were read 2 months after the last application. Results wereevaluated according to change in size as follows: Group Response. a. Completeflattening (100% regression). b. Significant flattening (75-99% regression). c.Adequate flattening (50-74% regression). d. Inadequate flattening (less than50%). Patients were assessed for any complication of bleomycin (systemic aswell as local) and recurrence of keloids and hypertrophic scars. Regularfollow-up for side-effects was done for 18 months. Out of 50 patients, complete flattening was observed in 22 cases (44%);significant flattening in 11 cases (22%); and adequate flattening was observedin 7 cases (14%). Only 10 cases (20%) did not show any satisfactory flattening.Pruritus was relieved completely in 40 patients (88.88%). Recurrence was seenin seven patients. They reached the conclusion that Bleomycin is easy toadminister, is cheap, shows high regression rate, and has minimum complicationand recurrence. Thus, it can be used as the first-line treatment modality formanagement of keloids and hypertrophic scars.
In a study by **NghiDinh Huu *et al****.* 2019 [37] Complete flattening was 70.8%, highly significantflattening was 8.3%, no patient of minimal flattening. Systemic side-effects ofbleomycin were not evaluated, but local side-effects were mainly pain (100%),blisters (78.3%), ulceration (5.8%), and hyperpigmentation (56.7%)
In another studyby **Khan HA *at el.*** 2019 [38]comparing
the efficacyof intralesional bleomycin versus intralesional triamcinoloneacetonide in the treatment of keloids A total of 164 patients wererandomized into two of 82 each. Group A received intralesional bleomycin andGroup B received intralesional triamcinolone. Patients were scored at baselineand at the end of treatment for therapeutic response based on reduction onpatient and observer scar assessment scale (POSAS). They inference that Intralesional bleomycin ismore efficacious than intralesional triamcinolone acetonide in the treatmentof keloids.
**D) GAP IN EXISTINGRESEARCH, PRESENT STATUS, UNRESOLVED ISSUES IF ANY**
There are many studies about use of cryotherapy in various form of keloidsand adverse effect related to its use. Most of the cases adverse effectsreported are oedema, swelling, blister formation, oozing, depigmentation. [15] Cryotherapy is a well-known single therapeuticmodality for keloids but with the constraints of being institutional basedtherapy where availability of cryogen, storage and application within astipulated time are major demerits of it.
Cryotherapyis not the sole agent for treatment of keloids. Intralesional injections, lasertreatment, pressure therapy, radiation and topical treatment have been proposedfor keloids. [7]
Intralesional bleomycin is arelatively newer treatment modality in the treatment of keloids. Bleomycin is acytotoxic antibiotic which induces apoptosis with sclerosing action on endothelialcells and inhibits collagen synthesis.[9] It is cheap, easy toadminister, show high regression rates and has minimum complications andrecurrences shown by some clinical trials. It has relatively low toxicity. Flulike symptoms have been reported after intralesional use but significantsystemic toxicity is rare. Local side effects of pain and swelling are commonwith intralesional use.[16]
Thus, the study evaluates the effectiveness, safety and patient friendliness(cost and quality of life) of cryotherapy versus Intralesional Bleomycin in thetreatment of localised keloids.
**METHODOLOGY**
**A)****STUDY DESIGN:** The study will bean institution based, open labelled, randomized control trial.
B) **STUDY SETTING ANDTIMELINES:** The study will be conducted at Dermatology Outdoor ofBankura Sammilani Medical College & Hospital, a rural based tertiary carehospital.
**STUDY POPULATION:** All patientsattending Dermatology OPD presenting with clinically diagnosed localisedkeloid.
**SAMPLE SIZE/DESIGN**: Calculated sample size is 23 in each arm considering excellent responsein 32.3% [31] patients withcryotherapy and 70.8% [37] with bleomycin, considering 5%alpha error and 20% power. Allowing 10%dropout rate the total sample size is 51.
The samples willbe drawn from study population who satisfies the inclusionand exclusion criteria.
**INCLUSION CRITERIA**
· Age more than 18 yrs. to 80 yrs.
· Previously not treated keloid
· Localised keloid
· Informed consent obtained
· Willing for once monthly treatment with spray cryotherapy orintralesional bleomycin injection.
**EXCLUSION CRITERIA**
· Keloid in children.
· Pregnant and lactating women.
· Infected or ulcerated keloid.
· Patients suffering from peripheral vascular disease.
· Raynaud’s phenomenon
· Concomitant immune defect, heart disease, renal failure, malignancy.
· Neurological or psychiatric disorders.
· Participation in any clinical trial within the last 3 months.
**SAMPLEDESIGN:**
**RANDOMIZATION:** Eligible participants after screeningwill be randomized into either group A (receiving cryotherapy) or group B (receiving intralesionalbleomycin) with allocation ratio 1:1 as per randomization sequence.Randomisation will be done by a computer-generated random number table into twoparallel group of 23 patients each by balanced unstratified randomization usingWinpepi software ETCETERA version 2.32 which is a WINPEPI (PEPI-for-windows)program.
**Allocation concealment:**
It will be done bysequentially numbered opaque sealed envelope (SNOSE) technique.
**STUDY MEDICATIONS:**
Group A (receiving cryotherapy)
GroupB (receiving intralesional bleomycin)
**I)****STUDY VARIABLES:**
1. Vancouver scar scale
2. The Patient and Observer scar assessment scale
3. Serial digital imaging
4. Biochemical and haematological parameters
5. DLQI
6. Cost of therapy
**J) DATA COLLECTION AND INTERPRETATION:** This study willbe conducted after getting permission from Institutional Ethics committee andapproval of West Bengal University of Health Sciences. All patients attendingDermatology OPD presenting with localised keloid will be included in the studybased on inclusion and exclusion criteria. Proper written informed consent fromeach patient shall be obtained after explaining the study procedure in theirown language.
**K)LABORATORY INVESTIGATIONS, PARAMETERS AND PROCEDURES:**
STUDY TOOLS
· Clinical history
· General survey and systemic examination
· Case record form (CRF)
· Adverse effect checklist.
· Complete hemogram (Hb, TC, DC, ESR, Platelets)
· Fasting blood sugar
· Urea, creatinine
· Liver function test
· Digital chest x-ray
· Slide callipers/Vernier callipers
· Digital camera
**PARAMETERS:**
**A.****Parameters forprimary objective (Effectiveness parameters):**
**VANCOUVER SCAR SCALE(VSS):**[39]
**B) Parameters for 1st secondary objectives****:**
**The Patient and Observer scar assessment scale (POSAS)[**41]
**C.Parameters for 2nd secondaryobjective (Safety parameters):**
a. The adverseevent complained by the patients
b. The adverseevent noted by the investigator
c. Biochemical, Haematologicalexamination findings
d. Visual painscale to asses pain associated with spray cryotherapy and intralesionalbleomycin injection.
**D. Parameter for 3rdsecondary objective**
Quality of life inpatients with keloid will be assessed by a validated vernacular (Bengali)version of Dermatology Life Quality Index(DLQI)[http://www.dermatology.org.uk/downloads/DLQI\_Bengali.pdf], whichconsists of 10 questions, each scored between 0 and 3.
**PROCEDURE/STUDYTECHNIQUE**
**Screening visit (-7 days)****:**
• Patientsdiagnosed clinically as a case of localised keloid will be screened. Generaland physical examination will be conducted.
•Informed consent will be obtained.
•Patient will be included in the study as per inclusion criteria.
• Baseline haematologicalinvestigations will be done – Routine hemogram, random blood sugar, urea,creatinine, liver function tests (LFT).
•Digital photographs will be taken.
**0 week (Baselinevisit)**:
• Patient will be enlistedas per inclusion and exclusion criteria.
•Effectiveness parameters will be noted.
• Patient will berandomised using the random number table.
•Digital photographs will be taken.
• Digital chestx-ray will be done for patient receiving bleomycin for baseline documentation.
• Patient will be provided regime ofeither group “A†or “B†for 20 weeks (according to randomization) and explainedabout the regime [ once every 4 weekly sittings of cryotherapy (Group A) andonce every 4 weekly intralesional bleomycin injection(Group B)]
• Thepatient will be asked to visit after 4 weeks.
**4th weekvisit****:**
•Effectiveness parameters will be noted.
•Digital photographs will be taken.
• The patient willbe inquired about the side effects of the therapies using a checklist.
• Patient will be provided regime ofeither group “A†or “B†[ cryotherapy (Group A) and intralesional bleomycininjection (Group B)]
• The patient willbe asked to visit after 4 weeks.
**8th, weekvisit****:**
**•** Same as 4th week visit**.**
• Thepatient will be asked to visit after 4 weeks.
**12thweekvisit:**
• Same as 4thweek visit.
• The patient willbe asked to visit after 4 weeks.
**16th weekvisit****:**
**•** Same as 4th week visit
• The patient willbe asked to visit after 4 weeks.
**20thweek visit ( End oftreatment visit):**
**•** Same as 4th week visit
• Baselinehaematological investigations will be done for both Group A and Group Bpatients – Routine hemogram, random blood sugar, urea, creatinine, liverfunction tests (LFT).
• The patient willbe asked to visit after 4 weeks
**24th weekvisit (Testing of cure visit):**
• Effectivenessparameters will be noted.
• The patient willbe inquired about the side effects of the drug using a checklist.
**•** Digital chest x-ray will be done forGroup B patients receiving bleomycin.
1. **L) OUTCOME DEFINITION:** This study is conducted as superiority trialdesign with the research hypothesis of "effectiveness of intralesionalbleomycin is better than cryotherapy in treatment of keloid". The adverseevent, quality of life and cost of therapy will also be evaluated and expectedthat they are better with intralesional bleomycin.
**M) OTHER ISSUES RELEVANT TO RESEARCH WORK:** For the presentstudy, the necessary particulars will be recorded and suited under thefollowing schedule proforma.
**STATISTICAL ANALYSIS PLAN**
**Plan for analysis of data:** The parametricdata will be analysed by using unpaired t-test or Mann Whitney *U* test(as applicable) and the non-parametric data will be analysed by using chi-squaretest. Medcalc® for windows version 10 will be used for statistical analysis and*P* value < 0.05 will be considered statistically significant. Graphpad prism software and Microsoft Office will be used for drawing thegraph.
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20. Naeini F,Najafian J, Ahmadpour K. Bleomycin tattooing as a promising therapeuticmodality in large keloids and hypertrophic scars. Dermatol Surg 2006;32:1023-30.
21. Wu W,Wang F, Yang K, et al. Dexamethasone induction of keloid regressionthrough effective suppression of VEGF expression and keloid fibroblastproliferation. J Invest Dermatol 2006; 126:1264-71.
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- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Not Yet Recruiting
- Sex
- All
- Target Recruitment
- 51
- 1 Age more than 18 yrs.
- 2 Previously not treated keloid 3 Localised keloid 4 Informed consent obtained 5 Willing for once monthly treatment with spray cryotherapy or intralesional bleomycin injection.
- 1 Keloid in children.
- 2 Pregnant and lactating women.
- 3 Infected or ulcerated keloid.
- 4 Patients suffering from peripheral vascular disease.
- 5 Raynaud’s phenomenon 6 Concomitant immune defect, heart disease, renal failure, malignancy.
- 7 Neurological or psychiatric disorders.
- 8 Participation in any clinical trial within the last 3 months.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method To assess effectiveness of Cryotherapy versus Intralesional Bleomycin injection in reducing the thickness of localised keloid. 6 months
- Secondary Outcome Measures
Name Time Method To assess the effectiveness of these two different methods in decreasing pain and itching associated with keloid. 6 months To assess tolerability and safety of the mentioned methods. 6 months To assess the improvement in quality of life with these mentioned methods 6 months
Trial Locations
- Locations (1)
Bankura Sammilani Medical College
🇮🇳Bankura, WEST BENGAL, India
Bankura Sammilani Medical College🇮🇳Bankura, WEST BENGAL, IndiaDr Prof Nilay Kanti DasPrincipal investigator9433394148drdasnilay@gmail.com