THESIS
TOPIC: Evaluation of Efficacy, Tolerability and safety,of Cryotherapy versus Intralesional bleomycin injection in the treatment
of localised keloids: An institution based open labelled randomised controlled
trial.
OBJECTIVE
OF RESEARCH
Primary objective:
To assess effectiveness of Cryotherapy versus Intralesional Bleomycin
injection in reducing the thickness of localised keloid.
Secondary objective:
a.
To assess the effectiveness of these two different methods in decreasing
pain 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-mentioned
methods.
BACKGROUND
OF RESEARCH:
A) RATIONALE OF STUDY: Keloids represent
a form of abnormal wound healing characterised by local fibroblast proliferation and excessive
collagen production in response to cutaneous injury.[3]For as long
as physicians and surgeons have intervened in attempts to influence and improve
keloids inability of any therapeutic
technique to achieve satisfactory scar reductions in all patients has been
uncomfortably apparent.[4,5,6]Numerous treatment options are
available, although the quality of evidence for their efficacy is generally
low, which should serve as an indication of
the lack of consistency and predictability in outcomes among various
treatment modalities.[7]
Numerous treatment methods, including
cryotherapy, intralesional injections, laser treatment, pressure therapy,
radiation and topical treatment have been proposed for keloids.[8]Deep
freezing of the keloids leads to necrosis, crusting and eventually diminution
of the lesion.[3]Intralesional bleomycin is a relatively newer and 2nd
or 3rd line therapy in treatment of keloids. Bleomycin induced apoptosis
with sclerosing action on endothelial cells inhibits collagen synthesis by
inhibiting the lysyl-oxidase enzyme and TGF-BETA.[9] Thus the study evaluates
the effectiveness, safety and patient friendliness (quality of life) of
Cryotherapy versus Intralesional Bleomycin injection in treatment of localised
keloid.
B) INTRODUCTION:
Keloids represent
an excessive connective tissue response to injury, which may be trivial. A
keloid is a benign well-demarcated overgrowth of fibrotic tissue which extends
beyond the original boundaries of a defect. They appear to be unique to humans
and the lack of an animal model has hampered studies into their pathogenesis. A
scar 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. Even
chemical trauma, from irritable herbal remedies can trigger keloid formation.
Sometimes keloid appears to develop spontaneously, particularly on the upper
chest. Introduction of foreign material, either exogenous such as suture
material, or endogenous, such as embedded hairs, is another risk factor.
Regression of keloids is a much slower process and keloids can expand gradually
over years.[1]
Patients
with keloid typically presents with pruritus, pain, ulceration, secondary
infection, restricted motion and psychological disturbance due to cosmetic
disfigurement.[10] Given their intractable nature and high
recurrence 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 treatment
methods, including cryotherapy, intralesional injections, laser treatment,
pressure therapy, radiation and topical treatment have been proposed for
keloids. [7]
Cryotherapy has been widely used for
years and is regarded as an effective modality for treatment of keloids;
several techniques and devices related to cryotherapy have been developed in
the clinical practice.[13,14]External cryotherapy, contact cryotherapy
with spray technique, is an efficient
and effective method for clinical use and has been performed over past few
years; however numerous side effects such as oedema, swelling, blister
formation, oozing, depigmentation are inevitably encountered during the wound
healing process.[15] Also infrastructural problems like procurement
of cryogen, storage and application within
a stipulated time are some major demerits of cryotherapy.
Bleomycin
is a cytotoxic antibiotic which induces apoptosis with sclerosing action on
endothelial cells and inhibits collagen synthesis by inhibiting the
lysyl-oxidase enzyme and TGF-BETA.[9] Bleomycin is available as a
powder and should be reconstituted with sterile saline to the desired
concentration. It is cheap, easy to administer, show high regression rates and
has minimum complications and recurrences shown by some clinical trials. In
dermatology intralesional bleomycin has largely been used in the treatment of
recalcitrant viral warts.[16] It has relatively low toxicity. Flu like
symptoms have been reported after intralesional use but significant systemic
toxicity is rare. Local side effects of pain and swelling are common with
intralesional use.[16]
C)REVIEW OF
LITERATURE
Keloid scars have afflicted humans for many centuries, described as far
back as 3000 BC in the Edwin Smith papyrus.[17] Keloids are
proliferative scars, defined as benign mesenchymal tumours that extend beyond
the wound margin, that do not regress spontaneously and tend to recur following
excision.[18,19] They are characterized by extensive
intradermal 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 includes
Africans, Asians and Hispanics. [21,22] Although benign, keloid
lesions can cause pain, paraesthesia and pruritus, as well as functional and
aesthetic impairment. Consequently, patients may be burdened with marked
physical and psychosocial sequelae.[23]
Many studies have examined the pathophysiology of keloid scarring at the
cellular level, but at present the exact underlying mechanisms are yet to be
comprehensively understood. Many factors such as wound tension, skin
pigmentation, genetic predisposition, immunoregulation and skin injury have
been implicated in the etiology of keloidogenesis.[21,24,25]
With little known regarding the exact pathophysiological events
underlying this condition, the management of a keloid scar is clinically
challenging. Many treatments have been advocated either alone or in
combination, including surgical excision, intralesional chemotherapeutic
injection, radiotherapy, laser therapy, cryotherapy, topical silicone, systemic
chemotherapy and pressure therapy, most of which have had varying and transient
success.[26,27,28] In addition, adverse effects from the
different treatments may significantly limit any benefits.[29]
Rusciani et
al. [30]1993 observed complete
flattening in 73% cases in their study of treatment of keloids using cryotherapy.
Side effects were limited to hypopigmentation
and slight to moderate atrophy in some cases.
In a study
by Zouboulis et al [31] in 1993, 93 patients
with keloid and hypertrophic scars were treated using cryosurgery without
injection. Excellent recovery, good recovery, and treatment failure were
32.35%, 29%, and 9.75%, respectively.
Indian study
conducted to assess the result of cryotherapy in small keloids by Sharma et al [32]
2007 found excellent response in 43.3%
patients, good result in 26.7% patients, fair and poor result in 16.7% and
13.3%, respectively. A better result in this study could be due to the fact
that they included only small lesions with depth less than 0.5 cm and gave
freeze-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 31
keloids and 5 hypertrophic scars with 3 to 5 intralesional infiltrations of
bleomycin within a 1-month period. Total regression was obtained in 84% of
scars.
In another
study, Espana et al.2001[34] injected
1.5 U/mL bleomycin into keloid and hypertrophic scars of 13 patients using a
multiple needle puncture approach. Patients received between 1-5 treatments;
each session held 1-4 months apart. All patients were relieved of pruritus
after 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% resolution
in scar thickness. At 12 months follow up, there was a 15.4% recurrence rate.
Using a different
approach, Saray and Gulec 2005[28] administered monthly
intralesional bleomycin (1.5 U/mL) into 15 keloid and hypertrophic scars using
a jet injector. Here, 73.3% of scars became completely flat and in the other
26.7% there was >50% reduction in thickness. During the mean follow up
period of 19 months, there were no reported recurrences.
More recently, Naeini et
al.2006[20] compared the efficacy of bleomycin tattoo
monotherapy with that of cryotherapy combined with intralesional triamcinolone
(TAC) injection. In the cryotherapy combined with TAC group, lesions less than
100 mm2 showed a significantly better response than larger
lesions (P=0.007), whereas in the bleomycin group, the size of lesion did not
affect the rate of resolution. There was no statistical difference between the
two 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 intralesional
bleomycin in skin of colour by Payapvipapong K et al. 2015 [35]
Twenty-six patients with keloids or hypertrophic scars were recruited. The
clinical improvement as assessed by the POSAS was not statistically
significant. In terms of patients satisfaction score, one half of both groups
reported a very good improvement. Photographic as well as ultrasonographic
evaluation showed no difference between the two groups. Bleomycin was found to
enter the blood circulation in a very small amount. There was no skin atrophy
detected in this study. They concluded that Intralesional bleomycin is a safe
and effective treatment for keloids and hypertrophic scars. The treatment is
comparable to intralesional triamcinolone. Unfortunately, hyperpigmentation was
the major side effect in darker skin type.
In a study by Aggarwal H et al. 2015 [36] they included 50 patients with keloids and
hypertrophic scars. Bleomycin was administered through multiple superficial
puncture 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 were
evaluated according to change in size as follows: Group Response. a. Complete
flattening (100% regression). b. Significant flattening (75-99% regression). c.
Adequate flattening (50-74% regression). d. Inadequate flattening (less than
50%). Patients were assessed for any complication of bleomycin (systemic as
well as local) and recurrence of keloids and hypertrophic scars. Regular
follow-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 observed
in 7 cases (14%). Only 10 cases (20%) did not show any satisfactory flattening.
Pruritus was relieved completely in 40 patients (88.88%). Recurrence was seen
in seven patients. They reached the conclusion that Bleomycin is easy to
administer, is cheap, shows high regression rate, and has minimum complication
and recurrence. Thus, it can be used as the first-line treatment modality for
management of keloids and hypertrophic scars.
In a study by Nghi
Dinh Huu et al.
2019 [37] Complete flattening was 70.8%, highly significant
flattening was 8.3%, no patient of minimal flattening. Systemic side-effects of
bleomycin were not evaluated, but local side-effects were mainly pain (100%),
blisters (78.3%), ulceration (5.8%), and hyperpigmentation (56.7%)
In another study
by Khan HA at el. 2019 [38]
comparing
the efficacy
of intralesional bleomycin versus intralesional triamcinolone
acetonide in the treatment of keloids A total of 164 patients were
randomized into two of 82 each. Group A received intralesional bleomycin and
Group B received intralesional triamcinolone. Patients were scored at baseline
and at the end of treatment for therapeutic response based on reduction on
patient and observer scar assessment scale (POSAS). They inference that Intralesional bleomycin is
more efficacious than intralesional triamcinolone acetonide in the treatment
of keloids.
D) GAP IN EXISTING
RESEARCH, PRESENT STATUS, UNRESOLVED ISSUES IF ANY
There are many studies about use of cryotherapy in various form of keloids
and adverse effect related to its use. Most of the cases adverse effects
reported are oedema, swelling, blister formation, oozing, depigmentation. [15] Cryotherapy is a well-known single therapeutic
modality for keloids but with the constraints of being institutional based
therapy where availability of cryogen, storage and application within a
stipulated time are major demerits of it.
Cryotherapy
is not the sole agent for treatment of keloids. Intralesional injections, laser
treatment, pressure therapy, radiation and topical treatment have been proposed
for keloids. [7]
Intralesional bleomycin is a
relatively newer treatment modality in the treatment of keloids. Bleomycin is a
cytotoxic antibiotic which induces apoptosis with sclerosing action on endothelial
cells and inhibits collagen synthesis.[9] It is cheap, easy to
administer, show high regression rates and has minimum complications and
recurrences shown by some clinical trials. It has relatively low toxicity. Flu
like symptoms have been reported after intralesional use but significant
systemic toxicity is rare. Local side effects of pain and swelling are common
with intralesional use.[16]
Thus, the study evaluates the effectiveness, safety and patient friendliness
(cost and quality of life) of cryotherapy versus Intralesional Bleomycin in the
treatment of localised keloids.
METHODOLOGY
A)
STUDY DESIGN: The study will be
an institution based, open labelled, randomized control trial.
B)
STUDY SETTING AND
TIMELINES: The study will be conducted at Dermatology Outdoor of
Bankura Sammilani Medical College & Hospital, a rural based tertiary care
hospital.
STUDY POPULATION: All patients
attending Dermatology OPD presenting with clinically diagnosed localised
keloid. SAMPLE SIZE/DESIGN: Calculated sample size is 23 in each arm considering excellent response
in 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 will
be drawn from study population who satisfies the inclusion
and 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 or
intralesional 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. SAMPLE
DESIGN: RANDOMIZATION: Eligible participants after screening
will be randomized into either group A (receiving cryotherapy) or group B (receiving intralesional
bleomycin) with allocation ratio 1:1 as per randomization sequence.
Randomisation will be done by a computer-generated random number table into two
parallel group of 23 patients each by balanced unstratified randomization using
Winpepi software ETCETERA version 2.32 which is a WINPEPI (PEPI-for-windows)
program. Allocation concealment: It will be done by
sequentially numbered opaque sealed envelope (SNOSE) technique. STUDY MEDICATIONS: Group A (receiving cryotherapy) Group
B (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 will
be conducted after getting permission from Institutional Ethics committee and
approval of West Bengal University of Health Sciences. All patients attending
Dermatology OPD presenting with localised keloid will be included in the study
based on inclusion and exclusion criteria. Proper written informed consent from
each patient shall be obtained after explaining the study procedure in their
own 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 for
primary 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 secondary
objective (Safety parameters):
a. The adverse
event complained by the patients
b. The adverse
event noted by the investigator
c. Biochemical, Haematological
examination findings
d. Visual pain
scale to asses pain associated with spray cryotherapy and intralesional
bleomycin injection.
D. Parameter for 3rd
secondary objective
Quality of life in
patients 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], which
consists of 10 questions, each scored between 0 and 3.
PROCEDURE/STUDY
TECHNIQUE
Screening visit (-7 days):
• Patients
diagnosed clinically as a case of localised keloid will be screened. General
and physical examination will be conducted.
•
Informed consent will be obtained.
•
Patient will be included in the study as per inclusion criteria.
• Baseline haematological
investigations will be done – Routine hemogram, random blood sugar, urea,
creatinine, liver function tests (LFT).
•
Digital photographs will be taken.
0 week (Baseline
visit):
• Patient will be enlisted
as per inclusion and exclusion criteria.
•
Effectiveness parameters will be noted.
• Patient will be
randomised using the random number table.
•
Digital photographs will be taken.
• Digital chest
x-ray will be done for patient receiving bleomycin for baseline documentation.
• Patient will be provided regime of
either group “A†or “B†for 20 weeks (according to randomization) and explained
about the regime [ once every 4 weekly sittings of cryotherapy (Group A) and
once every 4 weekly intralesional bleomycin injection
(Group B)]
• The
patient will be asked to visit after 4 weeks.
4th week
visit:
•
Effectiveness parameters will be noted.
•
Digital photographs will be taken.
• The patient will
be inquired about the side effects of the therapies using a checklist.
• Patient will be provided regime of
either group “A†or “B†[ cryotherapy (Group A) and intralesional bleomycin
injection (Group B)]
• The patient will
be asked to visit after 4 weeks.
8th, week
visit:
• Same as 4th week visit.
• The
patient will be asked to visit after 4 weeks.
12thweek
visit:
• Same as 4th
week visit.
• The patient will
be asked to visit after 4 weeks.
16th week
visit:
• Same as 4th week visit
• The patient will
be asked to visit after 4 weeks.
20thweek visit ( End of
treatment visit):
• Same as 4th week visit
• Baseline
haematological investigations will be done for both Group A and Group B
patients – Routine hemogram, random blood sugar, urea, creatinine, liver
function tests (LFT).
• The patient will
be asked to visit after 4 weeks
24th week
visit (Testing of cure visit):
• Effectiveness
parameters will be noted.
• The patient will
be inquired about the side effects of the drug using a checklist.
• Digital chest x-ray will be done for
Group B patients receiving bleomycin.
1.
L) OUTCOME DEFINITION: This study is conducted as superiority trial
design with the research hypothesis of "effectiveness of intralesional
bleomycin is better than cryotherapy in treatment of keloid". The adverse
event, quality of life and cost of therapy will also be evaluated and expected
that they are better with intralesional bleomycin. M) OTHER ISSUES RELEVANT TO RESEARCH WORK: For the present
study, the necessary particulars will be recorded and suited under the
following schedule proforma. STATISTICAL ANALYSIS PLAN
Plan for analysis of data: The parametric
data 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-square
test. Medcalc® for windows version 10 will be used for statistical analysis and
P value < 0.05 will be considered statistically significant. Graph
pad prism software and Microsoft Office will be used for drawing the
graph. REFERENCES:
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