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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 34  |  Issue : 2  |  Page : 98-101

Combined cryotherapy and topical 5-fluorouracil for treatment of basal cell carcinoma


1 Dermatology Unit, Department of Medical Applications of Laser, National Institute of Laser Enhanced Sciences (NILES), Cairo University, Cairo, Egypt
2 Cairo Hospital for Dermatology & Venereology, 'Al-Haud Al-Marsoud', Cairo, Egypt

Date of Submission29-Sep-2014
Date of Acceptance18-Nov-2014
Date of Web Publication29-Jan-2015

Correspondence Address:
Ahmed Sadek
MSc, 5 Lateef Basha Seelim St., Off AlNozha St., Heliopolis, 11341, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-6530.150259

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  Abstract 

Background
Cryotherapy (Cryo) and topical 5-fluorouracil (5FU) are both considered as successful noninvasive therapeutic options for basal cell carcinoma (BCC).
Objective
The aim of the study was to investigate the efficacy of combined Cryo and topical 5FU (Cryo+5FU) in patients suffering from BCC.
Design
This was a prospective clinical trial with a 6-month follow-up.
Duration
The study was carried out during a period of 11 months from March 2012 to February 2013.
Patients and methods
Fifteen patients complaining of BCC were included.
Intervention
Intervention included combined weekly regimen of Cryo followed after 3 days by twice daily 5FU application for four successive days for a maximum of 6 weeks.
Main outcome measures
Assessments of clinical improvement by examination, dermatological photography, and skin biopsy were the main outcome.
Results
All 15 patients achieved complete response with minimal side effects, good cosmetic outcome, and relatively shorter duration of treatment.
Conclusion
Combined Cryo+5FU offers a new effective modality for treatment of BCC.

Keywords: 5-fluorouracil, basal cell carcinoma, cryotherapy


How to cite this article:
Samy NA, Sadek A. Combined cryotherapy and topical 5-fluorouracil for treatment of basal cell carcinoma. Egypt J Dermatol Venerol 2014;34:98-101

How to cite this URL:
Samy NA, Sadek A. Combined cryotherapy and topical 5-fluorouracil for treatment of basal cell carcinoma. Egypt J Dermatol Venerol [serial online] 2014 [cited 2017 Jun 28];34:98-101. Available from: http://www.ejdv.eg.net/text.asp?2014/34/2/98/150259


  Introduction Top


Basal cell carcinoma (BCC) is the commonest skin cancer in Caucasians, and its incidence continues to increase worldwide [1]. First described in 1824 by Jacob [2], it is a slow-growing, locally destructive, skin tumor of the epidermis. It accounts for about 75-80% of nonmelanoma skin cancers [3]. There are four major distinctive clinicopathologic types, namely nodular, superficial, morpheaform, and fibroepithelial [4]. Highly efficient treatment modalities such as surgery, radiotherapy, curettage, cryotherapy (Cryo), photodynamic therapy, and topical applications of imiquimod or topical 5-fluorouracil (5FU) are available and effective for the great majority of BCC patients [5].


  Patients and methods Top


Patients and lesions

Fifteen adult patients suffering from BCC were enrolled in the study over a period of 11 months starting from March 2012 to February 2013. They were all diagnosed clinically and confirmed histopathologically. Thirteen had nodular type, one had morpheaform type, and one had the superficial type. They had mean age of 57.5 ± 6.25 years and were all men. Patients were excluded from the study for any of the following reasons: ischemic heart diseases, uncontrolled diabetes mellitus, past history of recurrent or metastatic nonmelanoma skin cancers, pregnancy or breast feeding, or participation in any other investigational study in the last 30 days. In addition, lesions were excluded, if they had been treated within 4 weeks or had highly infiltrating morphology as assessed clinically or histologically. Before proceeding with the treatment sessions, written informed consent was signed by each patient.

Histological examination

Every patient was examined, photographed, and a 3-5 mm punch biopsy was performed under local anesthesia from the edge of the lesion before starting therapy. The specimens were embedded in paraffin, processed routinely, and stained with hematoxylin and eosin. Histopathological examination of the specimens confirmed the diagnosis of BCC in all patients. After therapy and a follow-up period of 6 months, biopsies were performed to confirm response and exclude recurrence.

Treatment regimen

The treatment plan was to perform a weekly cycle of combined Cryo+5FU in the form of a single session of two freeze-thaw cycles of liquid nitrogen Cryospray followed after 3 days by twice daily 5% 5FU cream application for four successive days, for a maximum of 6 weeks. The typical weekly cycle was performed as follows: the lesion was swabbed by sterile alcohol gauze then dried off using sterile gauze. Two freeze-thaw cycles of liquid nitrogen was sprayed, using the Brymill Cry-AC manufactured by Brymill Cryogenics Systems (Ellington, Connecticut, USA) on the target area (tumor and a perilesional margin of 5 mm), each lasting for 30 s, followed by twice daily antibiotic cream application for 3 days in cases of blistering, and then 4 days of twice daily topical 5% 5FU application. In our study, we used Efudex 5% cream manufactured by Valeant Pharmaceuticals, USA.


  Results Top


A total of 15 BCC patients completed the study. All patients were evaluated at baseline, during each session, and monthly for 6 months after treatment. At each treatment session, we had to decide whether the condition had improved or not and compared the patient's condition with baseline photograph. Clinical and histopathological images of some patients are shown in [Figure 1],[Figure 2] and [Figure 3].
Figure 1: Patient 7 (a) before treatment, (b) after three sessions, (c) after five sessions (complete response), and (d) at 6-month follow-up.

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Figure 2: Patient 8 (a) before treatment, (b) after three sessions, (c) after five sessions (complete response), and (d) histopathology before treatment.

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Figure 3: Patient 9 (a) before treatment, (b) after four sessions, (c) after treatment (complete response), and (d) histopathology before treatment.

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Primary clinical response

Improvement was assessed clinically at each visit. Clinical response to therapy was clinically evaluated as follows: complete response (CR) was defined as the absence of a clinically evident lesion at the treatment site; partial response was defined as a marked reduction (>50%) in tumor size; and no response was defined as insignificant reduction (<50%) in tumor size. In our study, 100% (n = 15) patients achieved CR, 60% (n = 9) achieved CR after three sessions, 27% (n = 4) achieved CR after four sessions, and 13% (n = 2) achieved CR after five sessions.

Cosmetic outcome

Cosmetic outcome was determined for all lesions, using a four-point scale, as follows:

  1. Excellent: no scarring, atrophy, or induration and slight or no redness or change in pigmentation compared with adjacent skin;
  2. Good: no scarring, atrophy, or induration and moderate redness or increase in pigmentation compared with adjacent skin;
  3. Fair: slight to moderate occurrence of scarring, atrophy, or induration; and
  4. Poor: extensive occurrence of scarring, atrophy, or induration.


In our study, we found that two (13%) patients had 'Excellent' outcome, 10 (67%) had 'Good' outcome, and three (20%) patients had 'Fair' outcome, whereas none showed 'Poor' outcome.

Side effects

They were minimal in the form of mild erythema and pruritus during the incubation period of the topical 5FU and mild-to-moderate pain during and for 10 min following Cryo.

Follow-up

For all patients, after achieving CR, monthly visits were performed for 6 months. At each follow-up visit, we had to decide whether the condition had relapsed or not and compared the lesion site with the photograph taken at CR. Punch biopsy from the site of the healed lesion was performed 3 months after the last session. None of them showed any clinical or histopathological signs of recurrence.


  Discussion Top


BCC is the most common human cancer and accounts for about two-third of all skin cancers in patients of mixed European descent [6]. BCC rarely metastasizes, and it is usually slow-growing. However, if left untreated, it may spread locally to the bone or other tissues beneath the skin [7]. Average life time risk of developing a BCC is Ნ30% in Caucasians and represents a significant public health issue [8]. BCC can be classified as nodular, superficial, and morpheaform, occurring at a rate of 79, 15, and 6%, respectively [7]. Diagnosis is usually clinical, and clinical features are dependent on the subtype of BCC [9]. Treatment modalities are various including surgical excision, Mohs micrographic surgery, radiotherapy, curettage and cautery, Cryo, photodynamic therapy, and imiquimod [10]. The choice for a treatment modality should depend on the site, the size, and whether the BCC shows indolent (sBCC or nBCC) or aggressive growth (infiltrative BCC or basosquamous carcinoma) [11]. Patients reluctant to consider any form of surgery or having coexisting medical conditions or drug medication may influence the choice between surgical and nonsurgical treatment [12]. On the basis of the previous data, in our study, we have conducted our proposed regimen of combined Cryo+5FU for 15 patients, all suffering from BCC; they were not suitable for invasive modalities of treatment - 'i.e. difficult-to-treat lesions' - as they either had lesions located on exposed areas of the face and scalp or just were reluctant to undergo surgical procedures.

Cryo is a versatile modality that is used for many benign, premalignant, and malignant lesions. The indications are related to the nature of the lesion and to the type of patient. More than 50 benign conditions in addition to premalignant lesions and in-situ malignancies are amenable to Cryo management [13]. Tissue injury is induced by cell freezing and by the vascular stasis that develops in the tissue after thawing [14]. The rate of cooling is the single most important factor in efficient cryonecrosis [15]. Recurrence rates for primary BCC vary with treatment modality. The 5-year recurrence rate for Cryo may be as low as 7.5%, if lesions are chosen judiciously [16]. Mallon and Dawber studied the virtues of one versus two freeze-thaw cycles for treatment of BCC and found that the double freeze-thaw cycle on the face achieved 95.3% cure rate, whereas the single cycle had 79.4% cure rate [17].

Regarding 5FU, it is a structural analog of thymine, halogenated with fluorine at position 5. It interferes with pyrimidine metabolism and action; thus, DNA synthesis is blocked. Topical 5FU is commercially available as a solution (1, 2, and 5%) and as a cream (0.5, 1, and 5%). Side effects of the topical preparation are generally local cutaneous reactions of irritation, erythema, pain, swelling, pruritus, hyperpigmentation and hypopigmentation, allergic contact dermatitis, and photosensitivity. Unusual reactions may include onycholysis, onychodystrophy, and the appearance of telangiectasias [18]. Successful use of topical 5FU has been reported in many skin diseases; however, its use is most established in the treatment of actinic keratosis, particularly in patients with many lesions [19]. BCCs have been extensively investigated for treatment with topical 5FU. Some researchers report adequate tumor clearance [20], but others find unacceptable recurrence rates and persistence of tumor on biopsy [21]. Continuous topical 5FU under occlusion can be given for 2-3 days/week for about 16 weeks or until clearance occurs [22]. Persechino and colleagues described a 69-year-old White woman, with a large, ulcerous sBCC on the left breast; she was treated by five cycles of topical 5FU, 20 days each cycle, 1 month apart. Complete recovery came after about 1 year [23]. In addition, Gross and colleagues in 2007 concluded that 5% 5FU is a highly effective and well-tolerated treatment option for sBCCs offering a generally good cosmetic outcome and high levels of patient satisfaction [24].

Combination therapies have long been used to improve efficacy and decrease side effects and overall duration of treatment, as in successful treatment of nBCC with Cryo and reduced protocol of imiquimod 5% five times weekly for 6 weeks [25]. Messeguer and colleagues in 2012 concluded that Cryo applied to treat imiquimod-refractory BCCs seems to sensitize the tumor to the effect of the drug, thus reducing the percentage of patients who need surgery after an incomplete response to imiquimod [26]. In addition, the addition of retinoids to 5FU 5% cream has been reported in the treatment of disseminate actinic keratosiss and was found to be highly effective [27].

Concerning Cryo+5FU treatment of BCC, we used Medline database and Pubmed search engine utilizing the keywords 'Cryo, basal, fluorouracil' to search for any similarly proposed regimens, and it revealed a single case report about combined use of Cryo+5FU by Tsuji and colleagues in 1993, who reported a 58-year-old man with basal cell nevus syndrome who had variously sized BCCs, mostly of the superficial type, on his chest, back, and lumbar areas. Cryo alone or 5FU alone could not clear BCC but Cryo+5FU could. These results suggest that the Cryo+5FU was the most effective of these therapies [28]. In our study, using weekly cycles of combined Cryo+5FU in the form of a single session of two freeze-thaw cycles of liquid nitrogen Cryospray, followed after 3 days by twice daily 5% 5FU cream application for four successive days, for a maximum of 5 weeks gave very promising results, which is a relatively very good time to achieve CR. In addition, cosmetic outcome was overall rated as being 'Good', side effects were minimal, with no evidence of recurrence, both clinically and histopathologically, in all patients after 6-month follow-up duration.


  Conclusion Top


This study demonstrates that Cryo+5FU is an effective treatment method for BCCs with good cosmetic results. In addition, clinical results have shown that this treatment is safe and appears to provide long-term effect with considerable patient satisfaction in relatively overall treatment time. These results may offer new approach to the treatment of BCC in the future.


  Acknowledgements Top


Conflicts of interest

None declared.

 
  References Top

1.
Bath-Hextall F, et al. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev, 2007; 1 .  Back to cited text no. 1
    
2.
Jacob A. Observations respecting an ulcer of peculiar character, which attacks the eye-lids and other parts of the face. 1827, cited in: Early clinical descriptions of skin cancer. R. Jackson, Can Med Assoc J 1973;109:906-908.  Back to cited text no. 2
    
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Samarasinghe V, Madan V, Lear JT. Focus on Basal cell carcinoma. J Skin Cancer 2011; 2011 :328615.  Back to cited text no. 10
    
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Telfer NR, Colver GB, Bowers PW. Guidelines for the management of basal cell carcinoma. British Association of Dermatologists. Br J Dermatol 1999; 141 :415-423.  Back to cited text no. 12
    
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Jaramillo-Ayerbe F. Cryosurgery in difficult to treat basal cell carcinoma. Int J Dermatol 2000; 39 :223-229.  Back to cited text no. 13
    
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Kuflik EG, Gage AA. The five-year cure rate achieved by cryosurgery for skin cancer. J Am Acad Dermatol 1991; 24 :1002-1004.  Back to cited text no. 16
    
17.
Mallon E, Dawber R. Cryosurgery in the treatment of basal cell carcinoma. Assessment of one and two freeze-thaw cycle schedules. Dermatol Surg 1996; 22 :854-858.  Back to cited text no. 17
    
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Goette DK. Topical chemotherapy with 5-fluorouracil. A review. J Am Acad Dermatol 1981; 4 :633-649.  Back to cited text no. 18
    
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Breza T, Taylor R, Eaglstein WH. Noninflammatory destruction of actinic keratoses by fluorouracil. Arch Dermatol 1976; 112 :1256-1258.  Back to cited text no. 19
    
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Klein E, et al. Tumors of the skin. XII. Topical 5-Fluorouracil for epidermal neoplasms. J Surg Oncol 1971; 3 :331-349.  Back to cited text no. 20
    
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Reymann F. Treatment of basal cell carcinoma of the skin with 5-fluorouracil ointment. A 10-year follow-up study. Dermatologica 1979; 158 :368-372.  Back to cited text no. 21
    
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Pearlman DL, Youngberg B, Engelhard C. Weekly pulse dosing schedule of fluorouracil: a new topical therapy for psoriasis. J Am Acad Dermatol 1986; 15 :1247-1252.  Back to cited text no. 22
    
23.
Persechino S, et al. Giant basal cell carcinoma: an old but effective therapy with 5FU. Eur J Dermatol 2011; 21 :287.  Back to cited text no. 23
    
24.
Gross K, Kircik L, Kricorian G. 5% 5-Fluorouracil cream for the treatment of small superficial Basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction. Dermatol Surg 2007; 33 :433-439; discussion 440.  Back to cited text no. 24
    
25.
Moutran R, et al. Treatment of nodular basal cell carcinoma with cryotherapy and reduced protocol of imiquimod. Cutis 2012; 90 :256-257.  Back to cited text no. 25
    
26.
Messeguer F, et al. A pilot study of clinical efficacy of imiquimod and cryotherapy for the treatment of basal cell carcinoma with incomplete response to imiquimod. J Eur Acad Dermatol Venereol 2012; 26 :879-881.  Back to cited text no. 26
    
27.
Sander CA, et al. Chemotherapy for disseminated actinic keratoses with 5-fluorouracil and isotretinoin. J Am Acad Dermatol 1997; 36 :236-238.  Back to cited text no. 27
    
28.
Tsuji T, Otake N, Nishimura M. Cryosurgery and topical fluorouracil: a treatment method for widespread basal cell epithelioma in basal cell nevus syndrome. J Dermatol 1993; 20 :507-513.  Back to cited text no. 28
    


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