Basal cell carcinoma

Anthony Ormerod; Sanjay Rajpara; Fiona Craig

. 2010 Apr 6;2010:1719.

Basal cell carcinoma

Anthony Ormerod ^1,^#, Sanjay Rajpara ^2,^#, Fiona Craig ^3,^#

PMCID: PMC2907592 PMID: 21718567

Abstract

Introduction

Basal cell carcinoma (BCC) is the most common form of skin cancer, predominantly affecting the head and neck, and can be diagnosed clinically in most cases. Metastasis of BCC is rare, but localised tissue invasion and destruction can lead to morbidity. Incidence of BCC increases markedly after the age of 40 years, but incidence in younger people is rising, possibly as a result of increased sun exposure.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions on treatment response/recurrence (within 1 year of therapy) in people with basal cell carcinoma? What are the effects of interventions on long-term recurrence (a minimum of 2 years after treatment) in people with basal cell carcinoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: cryotherapy/cryosurgery, curettage and cautery/electrodesiccation, fluorouracil, imiquimod 5% cream, photodynamic therapy, and surgery (conventional or Mohs' micrographic surgery).

Key Points

Basal cell carcinoma (BCC) is the most common form of skin cancer, predominantly affecting the head and neck, and can be diagnosed clinically in most cases.

Metastasis of BCC is rare, but localised tissue invasion and destruction can lead to morbidity.
Risk factors for BCC include tendency to freckle, degree of sun exposure, excessive sun-bed use, and smoking.
Incidence of BCC increases markedly after the age of 40 years, but incidence in younger people is rising, possibly as a result of increased sun exposure.

Excisional surgery is considered likely to be effective in treating BCC.

Similar treatment-response rates at 1 year after treatment have been reported for excisional surgery compared with curettage plus cryotherapy and photodynamic therapy.
Excisional surgery is associated with fewer adverse effects compared with photodynamic therapy and curettage plus cryotherapy, and seems to be associated with improved cosmetic results compared with curettage plus cryotherapy 1 year after treatment.
We can't compare the effectiveness of surgical excision with Mohs' micrographic surgery in treating recurrent BCC, but excisional surgery seems to be associated with more adverse effects compared with Mohs' micrographic surgery.

Cryotherapy, with or without curettage, photodynamic therapy, and curettage and cautery/electrodesiccation may be effective treatments for BCC in the short term (up to 1 year after treatment).

Cryotherapy alone seems as effective as photodynamic therapy for superficial and nodular BCCs, but photodynamic therapy may produce better cosmetic results compared with cryotherapy alone.
We don't know how cryotherapy with curettage compares with photodynamic therapy or cryotherapy alone.
Twofold treatments with photodynamic therapy performed 1 week apart with delta-aminolaevulinic acid (ALA-PDT) may be more effective than single treatments in the short term.
There seems to be no difference in effectiveness between ALA-PDT using a broadband halogen light source and ALA-PDT using a laser light source.

Imiquimod 5% cream may be beneficial for the treatment of superficial and nodular BCCs compared with placebo in the short term (within 6 months after starting treatment).

It seems that more-frequent application of imiquimod 5% improves response rates compared with lower-frequency regimens, but is also associated with increased frequency of adverse effects.

We don't know whether fluorouracil is effective in the short-term treatment of BCC.

Excisional surgery, cryotherapy alone, photodynamic therapy, and curettage and cautery/electrodesiccation are thought to be beneficial in preventing long-term recurrence of BCC.

We don't know whether imiquimod 5% and fluorouracil are effective in preventing BCC recurrence in the longer term (at or beyond 2 years' treatment).

About this condition

Definition

Basal cell carcinoma (BCC) is the most common cancer found in humans. It is a slow-growing, locally invasive, malignant epidermal skin tumour which mainly affects white people. Although metastasis is rare, BCC can cause morbidity by local tissue invasion and destruction, particularly on the head and neck. The clinical appearances and morphology are diverse, including nodular, cystic, ulcerated ("rodent ulcer"), superficial, morphoeic (sclerosing), keratotic, and pigmented variants. Most BCCs (85%) develop on the head and neck. Diagnosis: The diagnosis of BCC is made clinically in most cases. A biopsy is performed for histological diagnosis when there is doubt about clinical diagnosis, and when people are referred for specialised forms of treatment.

Incidence/ Prevalence

The reported incidence of BCC varies in the literature. The incidence was reported to be 788 per 100,000 population per year in 1995 in Australia, and 146 per 100,000 population per year in 1990 in the USA. A Dutch study reported an incidence of 200 per 100,000 population per year, whereas the incidence in the UK is reported to be lower, at about 100 cases per 100,000 population per year. Because of incomplete registration of cases, some of these estimates may be low. The incidence of BCC increases markedly after the age of 40 years, and the incidence in younger people is increasing, possibly as a result of increased sun exposure.

Aetiology/ Risk factors

The reported risk factors for developing BCC include fair skin, tendency to freckle, degree of sun exposure, excessive sun-bed use, smoking, radiotherapy, phototherapy, male gender, and a genetic predisposition. Although cumulative lifetime sunlight exposure is a major risk factor for the development of BCC, it does not accurately predict the frequency of BCC development at a particular site on its own. Other contributory factors are skin phototype (e.g., Fitzpatrick I and II), number of lifetime visits to tanning beds, number of pack years of smoking, and number of blistering sunburns. Immunosuppressed people are also at increased risk for non-melanoma skin cancer, including BCC. The risk increases with duration of immunosuppression, and about 16% of people with renal transplants develop BCC — a 10-fold increased risk compared with the general population. An autosomal-dominant condition, naevoid BCC syndrome (Gorlin's syndrome) is characterised by the occurrence of multiple BCCs and developmental abnormalities.

Prognosis

The following factors can affect prognosis: tumour size, site, type, growth pattern/histological subtype, failure of previous treatment (recurrence), and immunosuppression. BCCs in close proximity to important body structures can potentially increase morbidity as a result of local tissue invasion or recurrence, and so BCCs can be categorised based on their location as: high risk (nose, nasal-labial fold, eyelids and periorbital areas, lips, chin, and ears); medium risk (scalp, forehead, pre- and postauricular areas, and malar areas); and low risk (neck, trunk, and extremities). Histologically, micronodular, infiltrative, morphoeic, and basosquamous types of BCC are classed as high risk. Distant metastases are rare. Although some BCCs tend to infiltrate tissues in a three-dimensional manner, growth is usually localised to the area of origin. However, if left untreated, BCC can cause extensive tissue destruction with infiltration in deeper tissues, such as bone and brain. BCCs may remain small for years with little tendency to grow, grow rapidly, or proceed by successive spurts of extension of tumour and partial regression. Therefore, the clinical course of BCC is unpredictable.

Aims of intervention

Prevention of recurrence, complete excision, complete histological and clinical response, good cosmetic result, avoidance of adverse effects of treatment.

Outcomes

Treatment response: clinical or histological response within 1 year of treatment; recurrence: local clinical or histological recurrence by the specified time period (within 1 year of or at or beyond 2 years after treatment); cosmetic outcome; quality of life; adverse effects of treatment.

Methods

Clinical Evidence search and appraisal December 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to December 2009, Embase 1980 to December 2009, and The Cochrane Library (all databases), issue 4, 2009. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for all databases, Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, including open/non-blinded studies for non-drug interventions, and containing at least 20 individuals. Ideally, we would report studies in which people were followed up for longer term (up to 5 years). However, some studies have reported only shorter-term data. We have therefore separately reported studies that have reported longer-term data (for a minimum of 2 years) and those which have reported short-term outcomes (within 1 year of treatment). There was no maximum loss to follow-up specified. All RCTs included histologically confirmed BCC. We also searched (from 1986 to December 2009) for prospective cohort studies on surgery. In addition, we used a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table 1.

GRADE evaluation of interventions for basal cell carcinoma

Important outcomes	Treatment response, recurrence, cosmetic appearance, quality of life, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of interventions on treatment response/recurrence (within 1 year of therapy) in people with basal cell carcinoma?
2 (206)	Treatment response	Cryotherapy v photodynamic therapy	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and no ITT analysis
1 (118)	Recurrence rate	Cryotherapy v photodynamic therapy	4	–3	0	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and no ITT analysis
2 (206)	Cosmetic appearance	Cryotherapy v photodynamic therapy	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and no ITT analysis
1 (140)	Treatment response	Different regimens of curettage and cautery/electrodesiccation v each other	4	−3	0	0	0	Very low	Quality points deducted for sparse data, uncertainty about blinding, and incomplete reporting of results
7 (1248)	Treatment response	Imiquimod 5% cream v placebo	4	−1	0	0	0	Moderate	Quality point deducted for short follow-up
1 (20)	Treatment response	Imiquimod 5% cream plus curettage/electrodesiccation v curettage and cautery/electrodesiccation	4	−2	0	0	0	Low	Quality points deducted for sparse data and for incomplete reporting of results
7 (413)	Treatment response	Different regimens of imiquimod v each other	4	–1	0	0	0	Moderate	Quality point deducted for short follow-up
1 (32)	Recurrence	Different regimens of imiquimod v each other	4	–1	0	–1	0	Low	Quality point deducted for sparse data. Directness point deducted for uncertainty of effect (clinical response assessed rather than histological)
1 (20)	Cosmetic appearance	Imiquimod 5% cream plus curettage/electrodesiccation v curettage and cautery/electrodesiccation	4	−3	0	0	0	Very low	Quality points deducted for sparse data, uncertainty about blinding, and incomplete reporting of results
2 (183)	Treatment response	Imiquimod 5% cream with occlusion v without occlusion	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
3 (276)	Treatment response	Different types of photodynamic light source v each other	4	−1	0	−1	0	Low	Quality point deducted for methodological flaws in RCTs (subgroup analysis, incomplete blinding, incomplete reporting of results, and uncertainty about randomisation). Directness point deducted for variation in interventions compared
1 (83)	Cosmetic appearance	Different types of photodynamic light source v each other	4	−2	0	0	0	Low	Quality points deducted for sparse data and incomplete blinding
1 (96 BCCs)	Treatment response	Surgery v curettage plus cryotherapy	4	−2	0	0	0	Low	Quality points deducted for sparse data and for not specifying method of randomisation
1 (96 BCCs)	Cosmetic appearance	Surgery v curettage plus cryotherapy	4	−3	−1	0	0	Very low	Quality points deducted for sparse data, for not specifying method of randomisation, and for subjective assessment of outcome. Consistency point deducted for conflicting results
3 (463)	Treatment response	Surgery v photodynamic therapy	4	–2	0	0	0	Low	Quality points deducted for per-protocol analysis and no significance assessment
3 (463)	Recurrence	Surgery v photodynamic therapy	4	−2	–1	0	0	Very low	Quality points deducted for per-protocol analysis and no significance assessment. Consistency point deducted for no agreement between studies
2 (252)	Cosmetic appearance	Surgery v photodynamic therapy	4	−3	0	0	0	Very low	Quality points deducted for no significance assessment, uncertainty about blinding, and for per-protocol analysis
1 (565)	Cosmetic appearance	Different types of surgery v each other	4	−2	0	−1	0	Very low	Quality points deducted for incomplete reporting of results and for uncertainty about blinding. Directness point deducted for not being able to generalise to simple surgical excision without margin control
1 (20)	Treatment response	High-dose v low-dose fluorouracil	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (20)	Cosmetic appearance	High-dose v low-dose fluorouracil	4	−2	0	0	0	Low	Quality points deducted for sparse data and incomplete blinding
What are the effects of interventions on long-term recurrence (a minimum of 2 years after treatment) in people with basal cell carcinoma?
1 (118)	Recurrence	Cryotherapy v photodynamic therapy	4	–3	0	0	0	Very low	Quality points deducted for sparse data, incomplete results, and no ITT analysis
1 (118)	Cosmetic appearance	Cryotherapy v photodynamic therapy	4	–3	0	0	0	Very low	Quality points deducted for sparse data, incomplete results, and no ITT analysis
1 (88)	Recurrence	Surgery v curettage plus cryotherapy	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
2 (276)	Recurrence	Surgery v photodynamic therapy	4	−3	0	0	0	Very low	Quality points deducted for unclear assessor blinding, per-protocol analysis, and significance assessment not performed
1 (103)	Cosmetic appearance	Surgery v photodynamic therapy	4	−3	0	0	0	Very low	Quality points deducted for sparse data, uncertainty about blinding, and for per-protocol analysis
1 (565)	Recurrence	Different types of surgery v each other	4	−1	0	−1	0	Low	Quality point deducted for uncertainty about timing of excisions. Directness point deducted for not being able to generalise to simple surgical excision without margin control
1 (565)	Cosmetic appearance	Different types of surgery v each other	4	−2	0	−1	0	Very low	Quality points deducted for incomplete reporting of results, and for uncertainty about blinding. Directness point deducted for not being able to generalise to simple surgical excision without margin control

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Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

Fitzpatrick I and II skin phototypes: An individual's genetically determined cutaneous sunburning and tanning tendency after ultraviolet radiation exposure may be roughly graded by self-assessed, so called skin phototype, or Fitzpatrick's skin type. There are I to VI skin types based on the skin's ability to burn or tan on exposure to sun, and on constitutive pigmentation.
Low-quality evidence: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Mohs' micrographic surgery (MMS): is a surgical technique for the removal of certain cutaneous carcinomas that allows precise microscopic marginal control by using horizontal frozen sections. The tumour is removed layer by layer until the excision site is histologically clear.
Very low-quality evidence: Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Anthony Ormerod, University of Aberdeen, Aberdeen, UK.

Sanjay Rajpara, Aberdeen Royal Infirmary, Aberdeen, UK.

Fiona Craig, Aberdeen Royal Infirmary, Aberdeen, UK.

References

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BMJ Clin Evid. 2010 Apr 6;2010:1719.

Cryotherapy/cryosurgery for short-term treatment response

Summary

TREATMENT RESPONSE Cryotherapy plus curettage compared with surgery: We don't know whether curettage plus cryotherapy is more effective in reducing treatment-failure rates at 1 year in people with superficial and nodular basal cell carcinomas (BCCs) on the head and neck areas ( low-quality evidence ). Compared with photodynamic therapy: Cryotherapy and photodynamic therapy may be equally effective at improving clinical and histological response rates at 3 and 12 months in people with superficial or nodular BCCs on the head, neck, legs, and arms (low-quality evidence). RECURRENCE RATE Compared with photodynamic therapy: Cryotherapy and photodynamic therapy may be equally effective at reducing recurrence rates in people with superficial BCCs on all body sites at 1 year ( very low-quality evidence ). COSMETIC APPEARANCE Cryotherapy plus curettage compared with surgery: We don't know whether curettage plus cryotherapy is more effective at producing better cosmetic results at 1 year in people with head and neck BCCs less than 2 cm in diameter ( very low-quality evidence ). Compared with photodynamic therapy: Cryotherapy may be less effective at improving cosmetic results in people with superficial or nodular BCCs on the head, neck, legs, and arms at 3 months to 1 year (low-quality evidence).

Benefits

Cryotherapy alone versus surgery:

We found no systematic review or RCTs comparing cryotherapy alone versus surgery.

Cryotherapy plus curettage versus surgery:

See benefits of surgery (conventional or Mohs' micrographic surgery) for short-term treatment response.

Cryotherapy versus curettage and cautery/electrodesiccation:

We found no systematic review or RCTs comparing cryotherapy versus curettage and cautery/electrodesiccation.

Cryotherapy versus imiquimod 5% cream:

We found one systematic review (search date 2006), which identified no RCTs comparing cryotherapy versus imiquimod cream.

Cryotherapy versus photodynamic therapy:

We found one systematic review (search date 2006), which identified two RCTs comparing cryotherapy versus photodynamic therapy. One of the RCTs was reported in two articles only in abstract form, and is therefore not discussed further. The second RCT identified by the review (88 people with superficial or nodular basal cell carcinomas (BCCs) on the head, neck, legs, and arms) found no significant difference in histological response rates at 1 year between photodynamic therapy and cryotherapy (see table 1 ). There was also no significant difference in clinical response rates at 1 year between photodynamic therapy and cryotherapy (see table 1 ). Cryotherapy consisted of two freeze–thaw cycles (each freeze lasting 25–30 seconds, with a thawing period of 2–4 minutes in between), depending on the size and thickness of the lesion. Photodynamic therapy was performed with delta-aminolaevulinic acid photodynamic therapy (ALA-PDT) after removing the stratum corneum. ALA-PDT was repeated at 4 weeks, 8 weeks, or 3 months after last treatment, if there was clinical or histological residual tumour growth. Cryotherapy was only repeated at 3 months if residual or recurrent BCC was clinically obvious. In total, 13/44 (30%) lesions in the ALA-PDT group were retreated compared with 1/39 (3%) in the cryotherapy group. One physician and two non-medical scientists (who were blinded to the intervention) assessed cosmetic outcome at 1 year using photographic and video documentation. The RCT found that cosmetic outcome was significantly worse 1 year after treatment with cryotherapy compared with ALA-PDT (see table 2 ).

Table 1.

RCTs of the effects of cryotherapy for short-term treatment response in people with basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Short-term treatment response rates
	1 RCT; 88 people with superficial or nodular BCCs	BCCs on head, neck, legs, and arms	Cryotherapy v photodynamic therapy	1 year	Proportion of treated lesions with histological evidence of tumour at 1 year: 11/44 (25%) with ALA-PDT v 6/39 (15%) with cryotherapy; RR 1.63, 95% CI 0.66 to 3.98
					Proportion of treated lesions with clinical evidence of tumour at 1 year: 2/44 (5%) with PDT v 5/39 (13%) with cryotherapy; RR 0.3, 95% CI 0.07 to 1.73
	118 people with 201 primary superficial BCCs	BCCs on any body site; diameter 6–15 mm on face or scalp, less than 20 mm on extremities or neck, and less than 30 mm on trunk	Cryotherapy v MAL-PDT	3 months	Proportion of lesions with early treatment failure: 5/98 (5%) with cryotherapy v 3/103 (3%) for MAL-PDT; P = 0.49 (per-protocol analysis)
				1 year	Proportion of lesions with recurrence at 1 year: 18/98 (18%) with cryotherapy v 12/103 (12%) with MAL-PDT; P value not reported

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BCC, basal cell carcinoma; ALA-PDT, 5-aminolaevulinic acid-photodynamic therapy; MAL-PDT, methyl aminolaevulinic acid photodynamic therapy

Table 1.

RCTs of the effects of cryotherapy on cosmesis in people with basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Cosmesis
	1 RCT; 88 people with superficial or nodular BCCs	BCCs on head, neck, legs, and arms	Cryotherapy v photodynamic therapy	1 year	Cosmetic outcome: ALA-PDT v cryotherapy: results presented graphically; P less than 0.001 for proportion of lesions with hypopigmentation, scar formation, or tissue defects; P less than 0.05 for hyperpigmentation
					Overall cosmetic outcome assessed as "excellent": 21/ 42 (50%) people with ALA-PDT v 3/37 (8%) people with cryotherapy; "good": 18/42 (43%) people with PDT v 17/37 (46%) people with cryotherapy; "acceptable": 1/42 (2%) people with ALA-PDT v 7/37 (19%) people with cryotherapy; "blemished": 2/42 (5%) people with ALA-PDT v 10/37 (27%) people with cryotherapy; P less than 0.001 for overall assessment
	118 people with 201 primary superficial BCCs	BCCs of any body site; diameter 6–15 mm on face or scalp, less than 20 mm on extremities or neck, and less than 30 mm on trunk	Cryotherapy v MAL-PDT	3 months	Proportion of BCCs assessed as having "excellent" cosmetic outcome by investigators: 4% for cryotherapy v 30% for MAL-PDT; P = 0.0005; proportion of BCCs assessed as having "excellent" cosmetic outcome by patients: 21% for cryotherapy v 45% for MAL-PDT; P value not reported
				1 year	Proportion of BCCs assessed as having "excellent" cosmetic outcome by investigators: 14% for cryotherapy v 39% for MAL-PDT; P value not reported; proportion of BCCs assessed as having "excellent" cosmetic outcome by patients: 30% for cryotherapy v 43% for MAL-PDT; P value not reported.

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ALA-PDT, 5-aminolaevulinic acid-photodynamic therapy; BCC, basal cell carcinoma; MAL-PDT, methyl aminolaevulinic acid photodynamic therapy.

We found one subsequent RCT (118 people with 201 primary superficial BCCs; tumours from all body sites and tumours of diameter 6–15 mm on the face or scalp, less than 20 mm on the extremities or neck, and less than 30 mm on the trunk were included) comparing cryotherapy (consisting of 2 freeze–thaw cycles, each freeze lasting 20 seconds, with a thawing period of 60 seconds) versus methyl aminolaevulinic acid photodynamic therapy (MAL-PDT) (given once at baseline, as this was prior to European regulatory approval of a 2-treatment regimen) for 3 months. BCCs not completely disappeared on clinical inspection 3 months after initial treatment were given a second cycle of the same treatment (except that MAL-PDT was administered twice on the second occasion). The RCT found no significant difference in treatment response between groups at 3 months after the last treatment (per-protocol analysis), or recurrence rates (reported as a proportion of the complete responders as opposed to overall cumulative failure rates, thus making the reported P values difficult to interpret) at 1 year (see table 1 ). The RCT included cosmetic outcomes assessed by investigators and patients. It did not state whether assessing investigators were blinded to the treatment allocation. The RCT found that cryotherapy was significantly less effective at improving cosmetic outcomes compared with MAL-PDT at 3 months on investigator assessments, and also on patient assessments (significance assessment not performed for patient-assessed outcomes) (see table 2 ).

Cryotherapy versus fluorouracil:

We found one systematic review (search date 2006), which identified no RCTs comparing cryotherapy versus fluorouracil.

Harms

Cryotherapy alone versus surgery:

We found no RCTs.

Cryotherapy plus curettage versus surgery:

See harms of surgery (conventional or Mohs' micrographic surgery) for short-term treatment response.

Cryotherapy versus curettage and cautery/electrodesiccation:

We found no RCTs.

Cryotherapy versus imiquimod 5% cream:

We found no RCTs.

Cryotherapy versus photodynamic therapy:

The second RCT identified by the review found that more people indicated pain and discomfort during and after treatment with ALA-PDT compared with cryotherapy, but the difference was reported as not statistically significant (absolute numbers and P values not reported; see table 3 ). There was a significantly shorter healing time after ALA-PDT compared with cryotherapy (absolute numbers not reported; P less than 0.001).

Table 1.

RCTs of adverse effects of interventions for basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Adverse effects
	1 RCT; 96 primary superficial or nodular BCCs	BCCs less than 2 cm in diameter, and located anywhere in the head and neck area	Surgery v curettage plus cryotherapy	Proportion of people with wound infection: 2/48 (4%) with surgery v 3/48 (6%) with curettage plus cryotherapy; P value not reported; moderate to severe swelling of the treated area with leakage of exudates from the defect: 0/48 (0%) with surgery v 42/48 (90%) with curettage plus cryotherapy; P value not reported
	100 primary BCCs in 88 people	BCCs of less than 20 mm diameter of the head and neck. Nodular or superficial histological subtype	Surgery v curettage plus cryotherapy	Proportion of people with wound infection requiring systemic antibiotics: 4/49 (8%) with surgery v 3/51 (6%) with surgery; P value not reported
	1 RCT; 118 primary nodular BCCs in 103 people	BCCs at all body sites, except mid-face region, orbital areas. Excluded lesions with a longest diameter of less than 6 mm or greater than 15 mm (face or scalp), greater than 20 mm (extremities or neck), or greater than 30 mm (trunk); and pigmented or morpheaform BCCs	Surgery v photodynamic therapy (MAL-PDT)	Proportion of people with any adverse effects: 14/49 (29%) with surgery v 27/52 (52%) with MAL-PDT; P = 0.03; burning sensation: 0/49 (0%) with surgery v 16/52 (31%) with MAL-PDT; pain in skin: 3/49 (6%) with surgery v 7/52 (14%) with MAL-PDT; erythema: 1/49 (2%) with surgery v 7/52 (14%) with MAL-PDT; skin infection: 3/49 (6%) with surgery v 0/52 (0%) with MAL-PDT; P values not reported for specific adverse effects
	173 primary nodular BCCs in 149 people	BCCs of less than 2 cm diameter, located anywhere except concave or hair-bearing sites	Surgery v ALA-PDT	Proportion of people with secondary wound infection: 1/83 (1%) with ALA-PDT v 0/88 (0%) with surgery; P value not reported
	196 people with primary superficial BCC	BCCs 8–20 mm diameter; located on any body site except mid-face region	Surgery v MAL-PDT	Proportion of people with adverse effects: 14/96 (15%) with surgery v 37/100 (37%) with MAL-PDT; P value not reported
	1 RCT; 408 primary BCCs in 374 people and 204 recurrent facial BCCs in 191 people	BCCs at least 1 cm in diameter, located in the H zone of the face; included aggressive histological subtype (morpheaform, micronodular BCC with squamous differentiation, trabecular, infiltrative)	Surgery with margin control v MMS	Complication rate after surgery for recurrent BCCs: 19/102 (19%) with surgery v 8/102 (8%) with MMS; P = 0.021
	408 primary BCCs in 374 people, 204 recurrent facial BCCs in 191 people	BCCs of at least 1 cm in diameter, located in the H zone of the face; included aggressive histological subtype (morpheaform, micronodular BCC with squamous differentiation, trabecular, infiltrative)	Surgery with margin control v MMS	Complication rate after surgery for primary BCCs: 27/199 (14%) with surgery v 24/198 (12%) with MMS; P = 0.681
	1 RCT, 88 people with superficial or nodular BCCs on the head, neck, legs, and arms		Cryotherapy v photodynamic therapy	More people indicated pain and discomfort during and after treatment with ALA-PDT v cryotherapy; difference reported as not significant; absolute numbers and P value not reported; significantly shorter healing time after ALA-PDT compared with cryotherapy; absolute numbers not reported; P less than 0.001
	118 people with 201 primary superficial BCCs	BCCs on any body site; diameter 6–15 mm on face or scalp, less than 20 mm on extremities or neck, and less than 30 mm on trunk	Cryotherapy v MAL-PDT	Proportion of people reporting any adverse effects: 79% with cryotherapy v 73% with MAL-PDT; local pain: 33% with cryotherapy v 37% with MAL-PDT; crusting: 47% with cryotherapy v 35% with MAL-PDT; erythema: 21% with cryotherapy v 30% with MAL-PDT; P values not reported
	72 people with nodular, superficial, or mixed BCCs		Imiquimod 5% cream v placebo (vehicle)	Proportion of people reporting at least 1 adverse effect: 15/36 (42%) with imiquimod 5% v 4/36 (11%) with placebo; P value not reported; application site reaction: 4/12 (33%) with imiquimod for 6 weeks v 0/36 (0%) with placebo; P value not reported
	1 RCT; 20 people with nodular BCCs	BCCs mostly located on the face and ears, and 4–17 mm in diameter	Imiquimod cream 5% plus C&D v C&D plus placebo	Proportion of healed lesions at 4 weeks: 40% with imiquimod plus C&D v 100% with C&D alone; P value not reported
	31 people with primary nodular BCCs	BCCs of the nose; less than 1 cm in diameter	Imiquimod 5% cream plus MMS v placebo cream plus MMS	Proportion of people with local inflammatory reactions at 6 weeks: 10/13 (77%) with imiquimod plus MMS v 2/16 (13%) with placebo plus MMS; P less than 0.001
	32 people with primary superficial BCCs	BCCs of any body site except anogenital area and within 1 cm of eyes, nose, mouth, or ears; minimum area of 0.5 cm² and maximum depth 2 mm	Imiquimod 5% cream once-daily dosing on alternate weeks for 8 weeks (regime 1) v once-daily dosing for 5 weeks with a 1-week interval after 2 weeks (regime 2)	Median composite visual analogue scores for tolerability over 8 weeks, ranging from 0 cm (not unpleasant) to 10 cm (absolutely intolerable): 0.85 cm with regime 1 v 0.30 cm with regime 2; P = 0.39
	1 RCT; 83 people with 245 superficial BCCs	All BCCs less than 1 mm thick with a diameter of less than 3 mm	ALA-PDT with laser light v ALA-PDT with broadband-lamp halogen light	Proportion of people with some discomfort during and after illumination: 83% with laser light v 76% with broadband light; P value not reported
	1 RCT; 154 people with 505 superficial BCCs	About 50% of BCCs diagnosed clinically and 50% by histology: subgroup analysis of histologically diagnosed BCCs only	Single v fractionated (twofold) ALA-PDT	Proportion of people requiring pain relief during or after treatment: 5/100 (5%) with single illumination v 15/55 (27%) with twofold illumination; P value not reported
	1 RCT; 39 people with 43 nodular BCCs	BCCs located anywhere on the body, except the periocular area and hairy scalp. All BCCs smaller than 20 mm	MAL-PDT v ALA-PDT	Intensity of pain during illumination using visual analogue score (scale of 0–10): first treatment cycle: 4.38 with ALA-PDT v 2.84 with MAL-PDT; P = 0.093; second treatment cycle: 4.83 with ALA-PDT v 3.89 with MAL-PDT; P = 0.403

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ALA-PDT, 5-aminolaevulinic acid-photodynamic therapy; BCC, basal cell carcinoma; C&D, curettage and electrodesiccation; MAL-PDT, methyl aminolaevulinic acid photodynamic therapy; MMS, Mohs' micrographic surgery

The subsequent RCT found minimal difference in the proportion of people reporting adverse effects, although statistical significance was not reported (see table 3 ).

Cryotherapy versus fluorouracil:

We found no RCTs.

Comment

Cryotherapy has been associated with treatment failure rates of 15% at 1 year for tumours involving all body sites and failure rates of 6% when combined with curettage for the treatment of BCCs in the head and neck area. However, in a study primarily looking at cosmetic outcome, cryotherapy had a failure rate of 7% (3/48) compared with 0% failure rate for surgery for head and neck tumours. There is limited evidence that cryotherapy is associated with inferior cosmetic results compared with surgery and either photodynamic therapies. Cryotherapy can be used for low-risk superficial or nodular BCCs smaller than 2 cm in diameter, but results are inferior to surgery.

Substantive changes

Cryotherapy (response/recurrence within 1 year of treatment): One RCT added comparing cryotherapy versus photodynamic therapy. The RCT found no difference between groups for treatment response at 3 months or rates of recurrence at 1 year. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Curettage and cautery/electrodesiccation for short-term treatment response

Summary

TREATMENT RESPONSE Curettage plus cryotherapy compared with surgery: We don't know whether curettage plus cryotherapy is more effective at reducing treatment-failure rates at 1 year in people with superficial and nodular basal cell carcinomas (BCCs) on the head and neck areas ( low-quality evidence ). Different regimens of curettage and cautery/electrodesiccation compared with each other: We don't know whether one session of curettage and electrodesiccation is more effective than three sessions of curettage and electrodesiccation at increasing histological clearance rates of nodular BCCs ( very low-quality evidence ). Curettage and cautery/electrodesiccation alone compared with curettage and cautery/electrodesiccation plus imiquimod 5% cream: Curettage and cautery/electrodesiccation alone may be less effective at histologically clearing tumours at 8 weeks in people with nodular BCCs (low-quality evidence). COSMETIC APPEARANCE Curettage plus cryotherapy compared with surgery: We don't know whether curettage plus cryotherapy is more effective at producing better cosmetic results at 1 year in people with head and neck BCCs less than 2 cm in diameter ( very low-quality evidence ). Curettage and cautery/electrodesiccation alone compared with curettage and cautery/electrodesiccation plus imiquimod 5% cream: We don't know whether curettage and cautery/electrodesiccation alone is more effective at improving cosmetic appearance in people with nodular BCCs (very low-quality evidence). NOTE We found no clinically important results from RCTs about treatment-response rates of curettage and cautery/electrodesiccation compared with other interventions in the treatment of people with BCC. There is consensus that curettage and cautery/electrodesiccation is effective in the treatment of BCC.

Benefits

Curettage and cautery/electrodesiccation alone versus surgery:

We found no systematic review, RCTs, or cohort studies comparing curettage and cautery/electrodesiccation versus surgery.

Curettage plus cryotherapy versus surgery:

See benefits of surgery (conventional or Mohs' micrographic surgery) for short-term treatment response.

Curettage and cautery/electrodesiccation versus cryotherapy:

We found no systematic review, RCTs, or cohort studies comparing curettage and cautery/electrodesiccation versus cryotherapy.

Curettage and cautery/electrodesiccation versus imiquimod 5% cream:

We found no systematic review, RCTs, or cohort studies comparing curettage and cautery/electrodesiccation alone versus imiquimod 5% cream. We found one RCT comparing curettage and electrodesiccation (C&D) plus imiquimod 5% cream versus C&D plus placebo: see benefits of imiquimod 5% cream.

Curettage and cautery/electrodesiccation versus photodynamic therapy:

We found no systematic review, RCTs, or cohort studies comparing curettage and cautery/electrodesiccation versus photodynamic therapy.

Curettage and cautery/electrodesiccation versus fluorouracil:

We found no systematic review, RCTs, or cohort studies comparing curettage and cautery/electrodesiccation versus fluorouracil.

Different regimens of curettage and cautery/electrodesiccation versus each other:

We found one RCT (158 nodular BCCs less than 2 cm in diameter from 140 people) comparing one session of C&D versus three sessions of C&D. The tumours were then excised using Mohs' micrographic surgery. The location of the tumours was not reported. The RCT found no difference in the rate of histological clearance between one and three sessions of C&D. The RCT found that, when evaluated for positive surgical margin, tumour present in the specimen, or both, there was no significant difference between the one-session or three-session groups (39/87 [45%] with 1-session C&D v 32/87 [37%] with 3-session C&D; statistical analysis between groups not performed; reported as not significant). Method of randomisation was unclear. Randomisation was by people, but the RCT reported outcomes by tumour (some people had more than 1 tumour).

Harms

Curettage and cautery/electrodesiccation alone versus surgery:

We found no RCTs.

Curettage plus cryotherapy versus surgery:

See harms of surgery (conventional or Mohs' micrographic surgery) for short-term treatment response.

Curettage and cautery/electrodesiccation versus cryotherapy:

We found no RCTs.

Curettage and cautery/electrodesiccation versus imiquimod 5% cream:

We found no RCTs comparing curettage and cautery/electrodesiccation alone with imiquimod 5% cream. We found one RCT comparing C&D plus imiquimod 5% cream versus C&D plus placebo. See harms of imiquimod 5% cream.

Curettage and cautery/electrodesiccation versus photodynamic therapy:

We found no RCTs.

Curettage and cautery/electrodesiccation versus fluorouracil:

We found no RCTs.

Different regimens of curettage and cautery/electrodesiccation versus each other:

The RCT gave no information about adverse effects.

Comment

We found no RCTs comparing C&D alone with other treatment modalities or with placebo. The RCT comparing different numbers of sessions of C&D found residual tumour in at least 30% of cases treated with one or three sessions of C&D. As the RCT compared different numbers of sessions of C&D, and there is no comparison with other interventions, there is insufficient evidence to decide about treatment response to C&D. There is evidence from retrospective studies that C&D results in 5-year cure rates for BCC of between 82% and 96%.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Imiquimod 5% cream for short-term treatment response

Summary

TREATMENT RESPONSE Compared with placebo: Imiquimod 5% cream applied for between 4 and 16 weeks seems more effective at reducing early histological treatment failure at 6 months in people with superficial and nodular basal cell carcinomas (BCCs) basal cell carcinomas at various sites on the body ( moderate-quality evidence ). Imiquimod 5% cream plus curettage and cautery/electrodesiccation compared with curettage and cautery/electrodesiccation alone: Imiquimod 5% cream plus curettage and cautery/electrodesiccation may be more effective at histologically clearing tumours at 8 weeks in people with nodular BCCs (low-quality evidence). Different regimens of imiquimod compared with each other: High-dose imiquimod 5% cream is more effective than low-dose regimens at reducing early histological treatment failure at 6 months in people with superficial or nodular BCCs (moderate-quality evidence). Imiquimod 5% cream with occlusion compared with imiquimod 5% cream without occlusion: Imiquimod 5% cream with occlusion seems as effective as imiquimod 5% cream without occlusion at reducing early histological treatment failure at 6 months in people with superficial or nodular BCCs (moderate-quality evidence) RECURRENCE RATES Different regimens of imiquimod compared with each other: Imiquimod 5% cream given more intensively for a shorter period may be more effective than longer, less-intensive regimens at reducing clinical recurrences at 1 year in people with superficial BCCs ( low-quality evidence ) COSMETIC APPEARANCE Imiquimod 5% cream plus curettage and cautery/electrodesiccation compared with curettage and cautery/electrodesiccation alone: We don't know whether imiquimod 5% cream plus curettage and cautery/electrodesiccation is more effective at improving cosmetic appearance in people with nodular BCCs ( very low-quality evidence ). ADVERSE EFFECTS Imiquimod 5% cream has been associated with local skin reactions such as vesicle formation, redness, oedema, erosion, ulceration, flaking, and scabbing, which decline in incidence and severity with less-frequent dosing.

Benefits

Imiquimod 5% cream versus placebo:

We found one systematic review with meta-analysis (search date 2006; 5 RCTs; 1145 people with superficial or nodular basal cell carcinomas [BCCs]) comparing imiquimod 5% cream versus placebo (vehicle cream). In the RCTs identified by the review, various rates of application of imiquimod 5% cream over 6 to 16 weeks were investigated. The review found that imiquimod 5% cream significantly reduced early treatment failure (measured histologically) within 6 months compared with placebo (see table 4 ).

Table 1.

RCTs of the effects of imiquimod 5% cream for short-term treatment response in people with basal cell carcinomas.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Short-term treatment response rates
	5 RCTs; 1145 people with superficial or nodular BCCs	Excluded BCCs on the anogenital area and tumours located within 1 cm of the hairline, nose, ears, mouth, and eyes. Most BCCs were 0.5–2.0 cm²	Imiquimod 5% cream v placebo (vehicle cream)	Within 6 months of treatment	Proportion of people with histological treatment failure: 135/636 (21%) with imiquimod v 483/509 (95%) with placebo; RR 0.25, 95% CI 0.19 to 0.32; P less than 0.00001
	1 RCT; 72 people with nodular, superficial or mixed BCCs		Different regimens of imiquimod 5% v placebo	Immediately after completion of 2, 4, or 6 weeks' treatment	Proportion of people with complete histological response: 3/12 (25%) with imiquimod 5% given for 2 weeks; absolute numbers not reported for placebo group; P = 0.09
					8/12 (67%) with imiquimod 5% given for 4 weeks; absolute numbers not reported for placebo group; P less than 0.01
					8/12 (67%) with imiquimod 5% for 6 weeks; absolute numbers not reported for placebo group; P less than 0.01
					Complete response in the pooled placebo group was 2/36 (6%)
	1 RCT; 20 people with nodular BCCs	BCCs mostly located on the face and ears, and 4–17 mm in diameter	Imiquimod cream 5% plus C&D v C&D plus placebo	8 weeks	Proportion of people with histological tumour clearance: 9/10 (90%) with imiquimod plus C&D v 6/10 (60%) with C&D alone; P value not reported
	31 people with primary nodular BCCs	BCCs of the nose; less than 1 cm in diameter	Imiquimod 5% cream plus MMS v placebo cream plus MMS	10 weeks	Proportion of people with histological clearance at MMS: 5/15 (33%) with imiquimod v 2/16 (13%) with placebo; P value not reported
	5 RCTs; 381 people with superficial or nodular BCCs		High-dose v low-dose imiquimod 5% cream	Within 6 months of treatment	Proportion of people with early histological treatment failure: 25/148 (17%) with high-dose imiquimod 5% v 86/233 (37%) with low-dose imiquimod 5%; RR 0.51, 95% CI 0.35 to 0.75; P = 0.0005
	1 RCT; 93 people with superficial BCC		High-dose (3 days/week) v low-dose imiquimod 5% (2 days/week) with occlusion	6 weeks	Proportion of people with complete histological response: 20/23 (87%) with high-dose imiquimod v 9/21 (43%) with low-dose imiquimod; P = 0.004
	32 people with primary superficial BCC	All body sites except anogenital sites or within 1 cm of eyes, nose, mouth, ears, or hairline	Once daily, alternate weeks for 8 weeks (regimen 1) v once daily for 5 weeks with a 1-week interval after 2 weeks (regimen 2)	19 weeks	Proportion or people with clinical tumour clearance: 9/14 (64%) with regimen 1 v 13/16 (81%) with regimen 2; OR 0.28, 95% CI 0.04 to 1.8; P = 0.21
				52 weeks	Proportion of people with clinical tumour clearance: 6/14 (43%) with regimen 1 v 14/16 (88%) with regimen 2; OR 0.12, 95% CI 0.02 to 0.72; P = 0.02
	2 RCTs: 1 RCT, 93 people with superficial BCC; 1 RCT, 90 people with nodular BCC		Imiquimod 5% cream with or without occlusion	Within 6 months of treatment	Superficial BCCs: proportion of people with early histological treatment failure: 15/54 (28%) with occlusion v 18/49 (37%) without occlusion; RR 0.76, 95% CI 0.43 to 1.33; P = 0.3
					Nodular BCCs: 21/45 (47%) with occlusion v 19/45 (42%) without occlusion; RR 1.11, 95% CI 0.70 to 1.76; P = 0.7

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BCC, basal cell carcinoma; C&D, curettage and electrodesiccation; MMS, Mohs' micrographic surgery

We found one additional RCT (72 people with nodular, superficial, or mixed BCCs) comparing different regimens of imiquimod 5% versus placebo. Imiquimod 5% or placebo was applied 5 days a week for 2, 4, or 6 weeks, after which the lesion was excised by Mohs' micrographic surgery (MMS). Complete response was defined as no histological evidence of BCC in the MMS excision specimen. The RCT found no significant difference between imiquimod 5% and placebo in the complete response rate after 2 weeks of treatment (see table 4 ). It found that imiquimod 5% given for 4 or 6 weeks significantly improved the complete response rate compared with placebo (see table 4 ).

We also found one small subsequent RCT (31 people with histologically confirmed nodular BCCs of the nose) comparing 5% imiquimod cream once daily for 6 weeks prior to MMS versus vehicle cream once daily for 6 weeks prior to MMS. Each topical treatment was applied nightly under occlusion. MMS was performed 4 weeks after the last topical treatment, by a single surgeon who was blinded to treatment allocation. The RCT found that a higher proportion of people were histologically free of tumour on complete tissue block sectioning at MMS with imiquimod 5% cream compared with placebo (significance assessment not reported) (see table 4 ).

Imiquimod 5% cream versus surgery:

We found one systematic review (search date 2006), which identified no RCTs comparing imiquimod 5% cream versus surgery.

Imiquimod 5% cream versus cryotherapy:

We found one systematic review (search date 2006), which identified no RCTs comparing imiquimod 5% cream versus cryotherapy.

Imiquimod 5% cream versus curettage and cautery/electrodesiccation:

We found no systematic review or RCTs comparing imiquimod 5% cream versus curettage and cautery/electrodesiccation.

Imiquimod 5% cream plus curettage and electrodesiccation versus placebo plus curettage and electrodesiccation:

We found one small RCT (20 people with nodular BCCs) comparing imiquimod 5% cream given once daily for 1 month after three cycles of curettage and electrodesiccation (C&D) versus placebo plus C&D. The RCT found that adding imiquimod 5% treatment to C&D increased histological tumour clearance at 8 weeks (P value not reported; see table 4 ). The RCT found no significant difference between the groups in cosmetic appearance at 8 weeks using the Vancouver scale (mean Vancouver scale score: 4.5 with imiquimod plus C&D v 4.2 with placebo plus C&D alone; P value not reported). The RCT did not report if investigators were blinded to treatment when assessing cosmetic outcome.

Imiquimod 5% cream versus photodynamic therapy:

We found one systematic review (search date 2006), which identified no RCTs comparing imiquimod 5% cream versus photodynamic therapy.

Imiquimod 5% cream versus fluorouracil:

We found one systematic review (search date 2006), which identified no RCTs comparing imiquimod 5% cream versus fluorouracil.

Different dosing regimens of imiquimod 5% cream versus each other:

We found one systematic review with meta-analysis (search date 2006; 5 RCTs; 381 people with superficial or nodular BCCs) comparing high-dose imiquimod 5% cream treatment (about once or twice daily) versus low-dose imiquimod 5% cream (about once or twice daily on 1–3 days a week) for up to 16 weeks. The review found that high-dose imiquimod 5% cream treatment significantly reduced early treatment failure (measured histologically) within 6 months compared with low-dose treatment (see table 4 ). Another RCT identified by the review but not included in the meta-analysis (93 people with superficial BCC) compared imiquimod 5% cream with or without occlusion given for either 2 or 3 days a week for 6 weeks. It found that imiquimod 5% cream with occlusion given for 3 days a week significantly increased the complete histological response rate at 6 weeks compared with the 2 days a week with occlusion regimen (see table 4 ).

We found one subsequent RCT (32 people with primary superficial BCCs from all body sites except anogenital sites or within 1 cm of eyes, nose, mouth, ears, or hairline were included) comparing two different dosing regimens of imiquimod 5% cream: regimen one (once-daily dosing on alternate weeks for 8 weeks) versus regimen two (once-daily dosing for 5 weeks with a 1-week interval after 2 weeks). The RCT found no significant difference in tumour clearance between the two regimens at 19 weeks (see table 4 ). However, the RCT found that regimen two (5 weeks with a 1-week interval) significantly decreased recurrence rates at 52 weeks compared with regimen 1 (alternate weeks for 8 weeks). Treatment response was assessed clinically but not histologically, which could be seen as a possible weakness of this study.

Imiquimod 5% cream with occlusion versus imiquimod 5% cream without occlusion:

We found one systematic review (search date 2006), which identified two RCTs comparing imiquimod 5% cream with occlusion versus imiquimod 5% cream without occlusion. Both RCTs were reported in the same article. The first RCT enrolled 93 people with superficial BCC, and the second RCT enrolled 90 people with nodular BCC. In both RCTs, imiquimod 5% cream was given for either 2 or 3 days a week, with or without occlusion, for 6 weeks. The review found that occlusion had no significant effect on early treatment failure rate for either imiquimod 5% cream dosing regimen compared with no occlusion. Early treatment failure within 6 months was measured histologically (see table 4 ).

Harms

Imiquimod 5% cream versus placebo:

The systematic review reported that local skin reactions were common with imiquimod 5% cream, and included redness, oedema, vesicles, erosion, ulceration, flaking, and scabbing. Local skin reactions were more common with more frequent applications. The additional RCT found that more people given imiquimod 5% cream than placebo reported at least one adverse effect. The most frequently reported adverse effect was application-site reaction, which included discomfort, dryness, itching, pain, and swelling (see table 3 ). The subsequent RCT reported a significantly higher incidence of local inflammatory reactions (including erythema, blistering, erosions, and crusting) with imiquimod 5% cream than with placebo (see table 3 ).

Imiquimod 5% cream versus surgery:

We found no RCTs.

Imiquimod 5% cream versus cryotherapy:

We found no RCTs.

Imiquimod 5% cream versus curettage and cautery/electrodesiccation:

We found no RCTs.

Imiquimod 5% cream plus curettage and electrodesiccation versus placebo plus curettage and electrodesiccation:

The RCT found that fewer people given imiquimod 5% plus C&D had healed at 4 weeks compared with placebo plus C&D (40% with imiquimod plus C&D v 100% with placebo plus C&D alone; P value not reported). At 8 weeks, all excision sites were healed.

Imiquimod 5% cream versus photodynamic therapy:

We found no RCTs.

Imiquimod 5% cream versus fluorouracil:

We found no RCTs.

Different dosing regimens of imiquimod 5% cream versus each other:

The review reported that local skin reactions were common with imiquimod 5% cream, and included redness, vesicles, erosion, ulceration, flaking, and scabbing. Local skin reactions were more common with more frequent applications.

The additional RCT found similar rates of application site reactions with both regimens. Patient tolerability (assessed by composite visual analogue scale scores) was also similar between the two regimens. There were no systemic adverse effects (see table 3 ).

Imiquimod 5% cream with occlusion versus imiquimod 5% cream without occlusion:

The RCTs identified by the systematic review found that severe local skin reactions were reported more frequently with more frequent applications. Incidence of local skin reactions was higher in the occlusion group applying treatment 3 days a week compared with the non-occlusion group (significance not assessed). However, incidence of skin reaction was lower in the occlusion group applying treatment 2 days a week compared with the non-occlusion group (significance not assessed).

Comment

Although application-site reactions and local skin reactions are common, the treatment seems to be tolerated by most people. The complete response rates at 6 to 12 weeks after treatment were reported to be between 67% to 100% with five applications a week or more treatment with the imiquimod 5% cream for superficial and nodular BCCs. There is no good evidence that imiquimod is a useful adjunct to Mohs' micrographic surgery.

Substantive changes

Imiquimod 5% cream (response/recurrence within 1 year of treatment): Two RCTs added. The first RCT compared imiquimod 5% cream once daily for 6 weeks prior to Mohs' micrographic surgery (MMS) versus vehicle cream once daily for 6 weeks prior to MMS. The RCT found that a higher proportion of people were histologically free of tumour on complete tissue block sectioning at MMS with imiquimod 5% cream compared with placebo. The second RCT compared two different dosing regimens of imiquimod 5% cream, regimen one (once-daily dosing, on alternate weeks for 8 weeks) versus regimen two (once-daily dosing for 5 weeks with a 1-week interval after 2 weeks). The RCT found no significant difference in tumour clearance between the two regimens at 19 weeks, but found that regimen two decreased recurrence rates at 52 weeks. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Photodynamic therapy for short-term treatment response

Summary

TREATMENT RESPONSE Compared with cryotherapy: Photodynamic therapy and cryotherapy may be equally effective at improving clinical and histological response rates at 3 and 12 months in people with superficial or nodular BCCs on the head, neck, legs, and arms ( low-quality evidence ). Compared with surgery: Photodynamic therapy and surgery may be equally effective at reducing treatment failure rates for nodular and superficial BCCs on various body sites at 3 months (low-quality evidence). Different types of light source compared with each other: We don't know how different types of light source compare with each other (low-quality evidence). RECURRENCE Compared with surgery: Photodynamic therapy may be less effective at reducing recurrence of lesions in people with primary nodular or superficial BCCs on any body site except concave or hair-bearing sites at 1 year ( very low-quality evidence ). Compared with cryotherapy: Photodynamic therapy and cryotherapy may be equally effective at reducing recurrence rates in people with superficial BCCs on all body sites at 1 year (very low-quality evidence). COSMETIC APPEARANCE Compared with surgery: Photodynamic therapy (using methyl aminolaevulinate cream) may be more effective at improving cosmetic results at 1 year in people with nodular BCCs located anywhere on the body except the central area of the face (very low-quality evidence). Compared with cryotherapy: Photodynamic therapy may be more effective at improving cosmetic results in people with superficial or nodular BCCs on the head, neck, legs, and arms at 3 months to 1 year (low-quality evidence). Different types of light source compared with each other: We don't know whether laser light ALA-PDT is more effective than broadband-lamp light ALA-PDT at improving cosmetic appearance in people with BCCs (low-quality evidence). ADVERSE EFFECTS Photodynamic therapy may be associated with more adverse effects compared with surgery.

Benefits

Photodynamic therapy versus placebo:

We found one systematic review (search date 2006), which identified two RCTs comparing photodynamic therapy versus placebo for treatment response in people with basal cell carcinoma (BCC). The RCTs were reported only in abstract form and are therefore not discussed further.

Photodynamic therapy versus cryotherapy:

See benefits of cryotherapy versus photodynamic therapy.

Photodynamic therapy versus surgery:

See benefits of surgery versus photodynamic therapy.

Photodynamic therapy versus curettage and cautery/electrodesiccation:

We found no systematic review or RCTs comparing photodynamic therapy versus curettage and cautery/electrodesiccation.

Photodynamic therapy versus imiquimod 5% cream:

We found one systematic review (search date 2006), which identified no RCTs comparing photodynamic therapy versus imiquimod 5% cream.

Photodynamic therapy versus fluorouracil:

We found one systematic review (search date 2006), which identified no RCTs comparing photodynamic therapy versus fluorouracil.

Different types of photodynamic therapy versus each other:

We found one systematic review (search date 2006), which identified two RCTs of the effects of different types of photodynamic therapy on treatment response and cosmetic outcome. We found two additional RCTs. The first RCT identified by the review assessed non-melanoma tumours, including squamous cell carcinomas, and did not perform a subgroup analysis for BCC alone. The results from this RCT are therefore not discussed further. The second RCT (83 people with 245 superficial BCCs) identified by the review compared 5-aminolaevulinic acid-photodynamic therapy (ALA-PDT) with laser light versus ALA-PDT with broadband-lamp halogen light. The RCT assessed clinical response at 3 and 6 months after treatment, and the review performed an analysis of early treatment failure using these results. The RCT found no significant difference in response rates at 6 months after treatment between laser-light ALA-PDT and broadband-lamp light ALA-PDT (see table 5 ). All people received 15 minutes of local pretreatment with 99% dimethyl sulfoxide, followed by topical application of 20% ALA with dimethyl sulfoxide 2% and ethylenediaminetetraacetic acid 2% for 3 hours, before light exposure. Cosmetic results were assessed by two investigators, one of whom was blinded to treatment. Cosmetic outcome was scored on the basis of visible stigmata and discoloration: excellent = no stigmata; good = slightly visible; fair = moderate discoloration; or poor = strong discoloration of the treatment area. The review found no significant difference in cosmetic outcome at 6 months between laser-light ALA-PDT and broadband-lamp light ALA-PDT (see table 6 ).

Table 1.

RCTs of the effects of photodynamic therapy for short-term treatment response in people with basal cell carcinomas.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Short-term treatment response rates
	1 RCT; 83 people with 245 superficial BCCs	All BCCs less than 1 mm thick with a diameter of less than 3 mm	ALA-PDT with laser light v ALA-PDT with broadband-lamp halogen light	3 months	Proportion of lesions with complete clinical response (clinical absence of disease): 95/111 (86%) with laser light v 110/134 (82%) with broadband-lamp light; P = 0.49
					Early treatment failure: 16/111 (14%) with laser light v 24/134 (18%) with broadband-lamp light; RR 0.80, 95% CI 0.45 to 1.44; P = 0.5
	1 RCT; 154 people with 505 superficial BCCs	About 50% BCCs diagnosed clinically and 50% by histology: subgroup analysis of histologically diagnosed BCCs only	Single v fractionated (twofold) ALA-PDT	1 year	Histologically confirmed BCCs: proportion of lesions with complete clinical response: 85% with single illumination v 98% with twofold illumination; absolute numbers not reported; P = 0.0003
	1 RCT; 39 people with 43 nodular BCCs	BCCs located anywhere on the body, except the periocular area and hairy scalp. All BCCs less than 20 mm	MAL-PDT v ALA-PDT	8 weeks after second treatment cycle	Proportion of BCCs with incomplete histological clearance: 6/22 (27%) with 2 cycles of ALA-PDT v 6/21 (29%) with 2 cycles of MAL-PDT; P = 0.924

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ALA-PDT, 5-aminolaevulinic acid-photodynamic therapy; BCC, basal cell carcinoma; MAL-PDT, methyl aminolaevulinic acid photodynamic therapy.

Table 1.

RCTs of the effects of photodynamic therapy on cosmesis in people with basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Cosmesis
	1 RCT; 83 people with 245 superficial BCCs	All BCCs less than 1 mm thick with a diameter of less than 3 mm	ALA-PDT with laser light v ALA-PDT with broadband-lamp halogen light	6 months	Proportion of lesions scored as "good" to "excellent" by 2 investigators, 1 of whom was blinded to treatment: 80/95 (84%) with laser-light PDT v 102/110 (93%) with broadband-light PDT; RR 0.91, 95% CI 0.82 to 1.01; P = 0.06

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ALA-PDT: 5-aminolaevulinic acid-photodynamic therapy; BCC, basal cell carcinoma; PDT, photodynamic therapy.

The first additional RCT compared ALA-PDT using single illumination versus fractionated twofold illumination. A subgroup analysis of complete clinical response of only histologically confirmed BCCs was reported. The subgroup analysis found that fractionated twofold illumination significantly increased the relative complete clinical response at 1 year compared with single illumination (see table 5 ). People in the single-illumination group received a light fraction of 75 J/cm², whereas those in the twofold-illumination group received light fractions of 20 and 80 J/cm² at 4 and 6 hours after the ALA. Complete response was assessed as the absence of clinical visual BCC. The method of randomisation was not specified. The second additional RCT (39 people with 43 nodular BCCs) compared two cycles of ALA-PDT versus two cycles of methyl aminolaevulinic acid photodynamic therapy (MAL-PDT). The RCT found no significant difference in histological response to treatment at 8 weeks between ALA-PDT and MAL-PDT (see table 5 ).

Harms

Photodynamic therapy versus placebo:

The RCTs identified by the systematic review were reported in abstract form only and are therefore not discussed further.

Photodynamic therapy versus cryotherapy:

See harms of cryotherapy versus photodynamic therapy.

Photodynamic therapy versus surgery:

See harms of surgery versus photodynamic therapy.

Photodynamic therapy versus curettage and cautery/electrodesiccation:

We found no RCTs.

Photodynamic therapy versus imiquimod 5% cream:

We found no RCTs.

Photodynamic therapy versus fluorouracil:

We found no RCTs.

Different types of photodynamic therapy versus each other:

The RCT identified by the review found no significant difference between laser-light ALA-PDT and broadband-lamp light ALA-PDT in the proportion of people reporting adverse effects during and after illumination (see table 3 ). During the first week after treatment, 68% of people in the laser-light ALA-PDT group and 74% of people in the broadband-lamp light ALA-PDT group reported some degree of discomfort (stinging, itching, pain, suppuration, headache, sensation of warmth, or blushing). The first additional RCT found that more people given twofold illumination than single illumination required pain relief during or after treatment (see table 3 ). The second additional RCT found no significant difference in the intensity of pain during illumination between ALA-PDT and MAL-PDT (see table 3 ).

Comment

One-year treatment response rates with photodynamic therapy are comparable with those of cryotherapy and surgery. There is limited evidence that fractionated twofold illumination is better than single illumination with ALA-PDT. However, there is no difference between laser-light ALA-PDT and broadband-lamp light ALA-PDT. Efficacy of photodynamic therapy needs to be assessed in long-term follow-up data. Photodynamic therapy is associated with mild and transient adverse effects. Photodynamic therapy requires several hospital visits, and this may not suit all people with BCC.

Substantive changes

Photodynamic therapy (response/recurrence within 1 year of treatment): One RCT added comparing photodynamic therapy with cryotherapy. The RCT found no difference between groups for treatment response at 3 months, or rates of recurrence at 1 year. Two RCTs added comparing surgery versus photodynamic therapy. Both RCTs found no difference between groups for treatment response at 3 months, but that surgery decreased the risk of recurrence at 1 year. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Surgery (excisional or Mohs' micrographic surgery) for short-term treatment response

Summary

TREATMENT RESPONSE Compared with curettage plus cryotherapy: We don't know whether surgery is more effective at reducing treatment-failure rates at 1 year in people with superficial and nodular basal cell carcinomas (BCCs) on the head and neck areas ( low-quality evidence ). Compared with photodynamic therapy: Surgery and photodynamic therapy may be equally effective at reducing treatment failure rates for nodular and superficial BCCs on various body sites at 3 months (low-quality evidence). RECURRENCE Compared with photodynamic therapy: Surgery may be more effective at reducing recurrence of lesions in people with primary nodular or superficial BCCs on any body site except concave or hair-bearing sites at 1 year ( very low-quality evidence ). COSMETIC APPEARANCE Compared with curettage plus cryotherapy: We don't know whether surgery is more effective at producing better cosmetic results at 1 year in people with head and neck BCCs less than 2 cm in diameter (very low-quality evidence). Compared with photodynamic therapy: Surgery may be less effective at improving cosmetic results at 1 year in people with nodular or superficial BCCs located anywhere on the body except the central area of the face (very low-quality evidence). Different types of surgery versus each other: We don't know whether surgery with margin control (3 mm excision margins) is more effective than Mohs' micrographic surgery (MMS) at improving cosmetic results at 6 months in people with primary and recurrent facial BCCs (very low-quality evidence). ADVERSE EFFECTS Surgical excision is associated with more adverse effects compared with Mohs' micrographic surgery but less than photodynamic therapy.

Benefits

Surgery versus cryotherapy alone:

We found no systematic review, RCTs, or cohort studies comparing surgery versus cryotherapy alone.

Surgery versus curettage plus cryotherapy:

We found one systematic review (search date 2006), which identified one RCT (96 primary superficial or nodular basal cell carcinomas [BCCs]) comparing surgery (with a 3-mm excision margin) versus curettage plus cryotherapy. BCCs were smaller than 2 cm in diameter and located anywhere in the head and neck area. Thorough curettage was performed before cryotherapy, which consisted of two freeze–thaw cycles (each freeze lasting 20 seconds, with a thawing period of 60 seconds). The review found no significant difference in clinical treatment-failure rates at 1 year between surgery and curettage plus cryotherapy (see table 7 ). However, the study was too small to detect clinically important differences between the groups. Cosmetic results were assessed from photographs by participants and by a panel of professionals who were blinded to treatment. The method of randomisation was not specified. The RCT found that conventional surgical excision significantly improved cosmetic outcome at 1 year, as judged by clinical professionals and participants, compared with curettage plus cryotherapy (see table 8 ). However, the difference for participant assessment was not significant (P = 0.15). It found no significant difference in cosmetic outcome judged by a beautician between surgery and curettage plus cryotherapy (see table 8 ).

Table 1.

RCTs of the effects of surgery on short-term treatment response in people with basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Treatment response rates
	1 RCT; 96 primary superficial or nodular BCCs	BCCs less than 2 cm in diameter, located anywhere in the head and neck area	Surgery v curettage plus cryotherapy	1 year	Clinical treatment failure rates: 3/48 (6%) with cryotherapy v 0/48 (0%) with surgery; RR 7, 95% CI 0.37 to 131.96; P = 0.2
	1 RCT; 118 primary nodular BCCs in 103 people	BCCs at all body sites except mid-face region, orbital areas, and ears. Excluded lesions with a longest diameter of less than 6 mm or greater than 15 mm (face or scalp), greater than 20 mm (extremities or neck), or greater than 30 mm (trunk); and pigmented or morpheaform BCCs	Surgery v photodynamic therapy	3 months	Proportion of lesions with early treatment failure: 5/53 (9%) with MAL-PDT v 1/52 (2%) with surgery; RR 4.91, 95% CI 0.59 to 40.57; P = 0.1
			1 year	Proportion of lesions with recurrence at 1 year: 9/53 (17%) with MAL-PDT v 2/52 (4%) with surgery; RR 4.42, 95% CI 1.00 to 19.47; P = 0.05
	173 primary nodular BCCs in 149 people	BCCs less than 2 cm diameter, located anywhere except concave or hair-bearing sites	Surgery v ALA-PDT	3 months	Proportion of lesions with early treatment failure: 2/88 (2%) with surgery v 2/83 (2%) with ALA-PDT; P value not reported
				1 year	Proportion of lesions with recurrence at 1 year: 2% with surgery v 14% with ALA-PDT; P value not reported
	196 people with primary superficial BCC	BCCs 8–20 mm diameter; located any body site except mid-face region	Surgery v MAL-PDT	3 months	Proportion of lesions with early treatment failure: 1/118 (1%) with surgery v 10/128 (8%) with MAL-PDT; 95% CI –12.1 to +1.9 (per-protocol analysis)
				1 year	Proportion of lesions showing recurrence: 21/128 (16%) with MAL-PDT v 1/118 (1%) with surgery; P value not reported

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BCC: basal cell carcinoma; MAL-PDT: methyl aminolaevulinic acid photodynamic therapy; ALA-PDT: 5-aminolaevulinic acid photodynamic therapy

Table 1.

RCTs of the effects of surgery on cosmesis in people with basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Cosmesis
	1 RCT; 96 primary superficial or nodular BCCs	BCCs less than 2 cm in diameter, located anywhere in the head and neck area	Surgery v curettage plus cryotherapy	1 year	Proportion of treated tumours judged as having "good" cosmetic result by clinical professionals: 35/48 to 45/48 (73% to 94%) with surgery v 10/48 to 16/48 (21% to 33%) with cryotherapy; "fair" cosmetic result: 2/48 to 12/48 (4% to 25%) with surgery v 14/48 to 25/48 (29% to 52%) with cryotherapy; "bad" cosmetic result: 1/48 to 4/48 (2% to 8%) with surgery v 7/48 to 24/48 (15% to 50%) with cryotherapy; P less than 0.01 for each comparison
					Proportion of treated tumour sites judged as "good" cosmetic result by participants: 48/48 (100%) with surgery v 42/48 (88%) with cryotherapy; "fair" cosmetic result: 0/48 (0%) with surgery v 6/48 (13%) with cryotherapy; P less than 0.15
					Proportion of treated tumours judged as having "good" cosmetic result by beautician: 28/48 (58%) with surgery v 21/48 (44%) with cryotherapy; "fair" cosmetic result: 19/48 (40%) with surgery v 26/48 (54%) with cryotherapy; "poor" cosmetic result: 1/48 (2%) with surgery v 1/48 (2%) with cryotherapy; P = 0.35
	1 RCT; 118 primary nodular BCCs in 103 people	BCCs at all body sites except mid-face region, orbital areas, and ears. Excluded lesions with a longest diameter of less than 6 mm or greater than 15 mm (face or scalp), greater than 20 mm (extremities or neck), or greater than 30 mm (trunk); and pigmented or morpheaform BCCs	Surgery v photodynamic therapy	3 months	Proportion of BCCs assessed as having "excellent" or "good" cosmetic outcome by investigators: 36/44 (82%) with MAL-PDT v 15/45 (33%) with surgery; P = 0.001; proportion of BCCs assessed as having "excellent" or "good" cosmetic outcome by participants: 39/41 (95%) with MAL-PDT v 37/44 (84%) with surgery; P = 0.1
				1 year	Proportion of BCCs assessed as having "excellent" or "good" cosmetic outcome by investigators: 33/42 (79%) with MAL-PDT v 17/45 (38%) with surgery; P = 0.001; proportion of BCCs assessed as having "excellent" or "good" cosmetic outcome by participants: 41/42 (98%) with MAL-PDT v 36/43 (84%) with surgery; P = 0.03
				2 years	Proportion of BCCs assessed as having "excellent" or "good" cosmetic outcome by investigators: 24/29 (83%) with MAL-PDT v 16/39 (41%) with surgery; P = 0.001; proportion of BCCs assessed as having "excellent" or "good" cosmetic outcome by participants: 28/29 (97%) with MAL-PDT v 27/36 (75%) with surgery; P = 0.04
	196 people with primary superficial BCC	BCCs 8–20 mm diameter; located any body site except mid-face region	Surgery v MAL-PDT	3 months	Proportion of BCCs assessed as having "excellent" or "good" cosmetic outcome by investigators: 58% with surgery v 87% with MAL-PDT; proportion of BCCs assessed as having "excellent" or "good" cosmetic outcome by participants: 81% with surgery v 94% with MAL-PDT; P values not reported
	1 RCT; 408 primary BCCs in 374 people, 204 recurrent facial BCCs in 191 people	BCCs of at least 1 cm in diameter, located in the H zone of the face; included aggressive histological subtype (morpheaform, micronodular BCC with squamous differentiation, trabecular, infiltrative)	Surgery with margin control v MMS	Not reported	Mean defect size for primary BCCs: 4.64 cm² with surgery v 4.06 cm² with MMS; P = 0.386; mean defect size for recurrent BCCs: 7.78 cm² with surgery v 7.50 cm² with MMS; P = 0.598

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BCC, basal cell carcinoma; MAL-PDT, methyl aminolaevulinic acid photodynamic therapy; MMS, Mohs' micrographic surgery

Surgery versus curettage and cautery/electrodesiccation:

We found no systematic review, RCTs, or cohort studies comparing surgery versus curettage and cautery/electrodesiccation.

Surgery versus imiquimod 5% cream:

We found one systematic review (search date 2006), which identified no RCTs comparing surgery versus imiquimod cream.

Surgery versus photodynamic therapy:

We found one systematic review (search date 2006), which identified one RCT, and two subsequent RCTs. The RCT (118 primary nodular BCCs in 103 people) compared surgical excision versus photodynamic therapy using methyl aminolaevulinate cream (MAL-PDT). It included BCCs at all body sites except mid-face region, orbital areas, and ears. Lesions with a longest diameter of less than 6 mm or of more than 15 mm for the face or scalp, more than 20 mm for the extremities or neck, or more than 30 mm for the trunk were excluded from the RCT, as were pigmented or morpheaform BCCs. Surgical excision margins were at least 5 mm. MAL-PDT was given twice, 1 week apart. BCCs that had not completely disappeared on clinical inspection 3 months after initial MAL-PDT were given a second cycle of MAL-PDT. The review found no significant difference between surgery and MAL-PDT in the proportion of lesions with early treatment failure at 3 months or recurrence at 1 year (see table 7 ). At 1 year, two lesions that seemed disease free at 3 months after MAL-PDT showed evidence of disease, whereas all lesions cleared by surgery remained disease free. Only per-protocol analysis was reported. Cosmetic outcome was assessed by investigators and participants at 3, 12, and 24 months after surgery or last MAL-PDT treatment. The RCT did not state whether investigators were blinded to treatment when assessing cosmetic outcome. The RCT found that, compared with surgical excision, MAL-PDT significantly improved cosmetic outcome at 3 and 12 months on investigator assessment, and at 1 year on participant assessment (see table 8 ). Only per-protocol analysis was reported.

The first subsequent RCT (149 people with 173 nodular BCCs of 20 mm or less in diameter; BCCs were included from any body site except concave or hair-bearing sites) compared surgical excision versus 5-aminolaevulinic acid photodynamic therapy (ALA-PDT). The diagnosis was histologically confirmed by a punch biopsy of the thickest part of the lesion and surgical excision margins were at least 3 mm. People randomised to receive PDT had surgical debulking by curette 3 weeks before to the PDT treatment. The RCT found no significant difference between groups for treatment response at 3 months (see table 7 ), but at 1 year, surgery significantly reduced the risk of recurrence compared with ALA-PDT (see table 7 ). The risk of recurrence after PDT was significantly increased in tumours with a maximum thickness of 1.3 mm or more (42% failure rate v 16% in tumours less than 1.3 mm thick; absolute numbers not reported). This RCT did not report cosmetic outcomes.

The second subsequent RCT (196 people with primary superficial BCC) compared surgical excision versus methyl aminolaevulinic acid photodynamic therapy (MAL-PDT was given twice, 1 week apart). The RCT reported that surgical excision margins were at least 3 mm, and BCCs that had not completely responded at 3 months could be treated with a further cycle of MAL-PDT. The RCT found no significant difference between groups at 3 months for treatment response; however, at 1 year, surgery reduced the proportion of people with recurrence compared with MAL-PDT (recurrence rates in this study were reported as a proportion of the complete responders as opposed to overall cumulative failure rates, no significance assessment performed; see table 7 ). Cosmetic outcome was assessed by investigators and participants at 3, 6, and 12 months after treatment. The RCT did not state whether investigators were blinded to treatment allocation when assessing outcome. The RCT found that MAL-PDT significantly improved cosmetic outcome compared with surgery at 3 and 12 months by investigator assessment (see table 8 ).

Surgery versus fluorouracil:

We found one systematic review (search date 2006), which identified no RCTs comparing surgery versus fluorouracil.

Different types of surgery versus each other:

We found one systematic review (search date 2006), which identified one RCT (408 primary BCCs in 374 people and 204 recurrent facial BCCs in 191 people) comparing surgery with a 3-mm margin versus Mohs' micrographic surgery (MMS). Cosmetic results were assessed by participants, and by three professionals and three lay people, using photographs. The RCT did not state if investigators were blinded to treatment when assessing cosmetic outcome. The RCT found no significant difference in cosmetic outcome 6 months after treatment between surgical excision and MMS (absolute numbers and P value not reported). It found that cosmetic results became significantly worse with increasing defect size for primary and recurrent BCCs (P less than 0.001). However, there was no significant difference between surgical excision and MMS in the mean defect size for primary or recurrent BCCs (see table 8 ). The study included histologically confirmed BCCs of at least 1 cm in diameter, located in the H zone of the face, or an aggressive histological subtype (morpheaform, micronodular BCC with squamous differentiation, trabecular, infiltrative). If the resection margins were positive after surgical excision, a re-excision with a 3-mm margin was done, and, if the margins remained positive after re-excision, MMS was performed. The result of the RCT cannot be generalised to simple surgical excision without margin control.

Harms

Surgery versus cryotherapy alone:

We found no RCTs or cohort studies.

Surgery versus curettage plus cryotherapy:

The RCT identified by the review found that fewer people developed a wound infection with surgery compared with curettage plus cryotherapy, although people in the cryotherapy group reported swelling and exudation of the treated area (see table 3 ).

We found one additional RCT, which found that a slightly higher proportion of people having surgical excision required systemic antibiotics for wound infection, but the statistical significance of these results was not reported (see table 3 ).

Surgery versus curettage and cautery/electrodesiccation:

We found no RCTs or cohort studies.

Surgery versus imiquimod 5% cream:

We found no RCTs or cohort studies.

Surgery versus photodynamic therapy:

The review found significantly fewer adverse effects associated with surgery compared with MAL-PDT (see table 3 ). The RCT identified by the review found that more people reported transient local reactions, such as burning sensation of the skin, pain in the skin, or erythema, with MAL-PDT than with surgery, but reported no significance values for these adverse effects (see table 3 ).

The first subsequent RCT reported no significant differences in serious postoperative adverse effects between groups (see table 3 ). The second subsequent RCT reported a higher incidence of adverse effects with MAL-PDT compared with surgery (statistical significance not reported) (see table 3 ).

Surgery versus fluorouracil:

The review identified no RCTs.

Different types of surgery versus each other:

The RCT identified by the review found no difference in postoperative adverse events between surgery and MMS for primary BCCs. Long-term follow-up of the RCT included in the review reported significantly more adverse events after surgery with margin excision than after MMS for recurrent BCCs (see table 3 ). Adverse effects included wound infections, graft necrosis, postoperative bleeding, or a combination.

Comment

Surgery results in a good treatment response for superficial and nodular BCCs located at all body sites. There is limited evidence that surgery is associated with better cosmetic results compared with cryotherapy, similar cosmetic results compared with MMS, and worse cosmetic results compared with MAL-PDT.

Substantive changes

Surgery (response/recurrence within 1 year of treatment): Two RCTs added comparing surgery with photodynamic therapy. Both RCTs found no difference between groups for treatment response at 3 months, and that surgery decreased the risk of recurrence at 1 year. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Fluorouracil for short-term treatment response

Summary

TREATMENT RESPONSE High-dose fluorouracil compared with low-dose fluorouracil: High-dose fluorouracil seem as effective as low-dose fluorouracil at achieving complete histological responses after excision of lesions at 3 months in people with basal cell carcinomas (BCCs) ( moderate-quality evidence ). COSMETIC APPEARANCE High-dose fluorouracil compared with low-dose fluorouracil: We don't know whether high-dose fluorouracil is more effective at improving cosmetic results at 3 months in people with nodular BCCs ( low-quality evidence ). ADVERSE EFFECTS High doses of fluorouracil may cause more adverse effects compared with low doses.

Benefits

Fluorouracil versus placebo:

We found one systematic review (search date 2006), which identified no RCTs comparing the effects of fluorouracil versus placebo on treatment response rates in people with basal cell carcinoma (BCC).

Fluorouracil versus surgery:

We found one systematic review (search date 2006), which identified no RCTs comparing fluorouracil versus surgery.

Fluorouracil versus cryotherapy:

We found one systematic review (search date 2006), which identified no RCTs comparing fluorouracil versus cryotherapy.

Fluorouracil versus curettage and cautery/electrodesiccation:

We found no systematic review or RCTs comparing fluorouracil versus curettage and cautery/electrodesiccation.

Fluorouracil versus imiquimod 5% cream:

We found one systematic review (search date 2006), which identified no RCTs comparing fluorouracil versus imiquimod cream.

Fluorouracil versus photodynamic therapy:

We found one systematic review (search date 2006), which identified no RCTs comparing fluorouracil versus photodynamic therapy.

High-dose versus low-dose fluorouracil:

We found one systematic review (search date 2006), which identified two RCTs comparing high-dose versus low-dose fluorouracil. Both RCTs identified by the review did not meet Clinical Evidence inclusion criteria, and are therefore not discussed further. We found one additional RCT (20 people with nodular BCC) comparing higher-dose versus lower-dose intralesional fluorouracil given weekly for 4 to 6 weeks. The RCT found no significant difference in complete histological response between MPI 5003 0.5 mL (5-fluorouracil 15 mg) and MPI 5003 0.25 mL (5-fluorouracil 7.5 mg) after excision of the lesion at 3 months (see table 9 ). The RCT found no significant difference in cosmetic outcome between treatments as evaluated by investigators and participants at 3 months (see table 10 ). The RCT did not state if investigators were blinded to treatment when assessing cosmetic outcome. Evaluations ranged from "satisfactory" to "excellent", with at least 80% or all assessments rated as "very good" or "excellent". People with basal cell nevus syndrome or morpheaform, pigmented, and deeply invasive lesions were excluded from the RCT.

Table 1.

RCTs of the effects of fluorouracil for short-term treatment response in people with basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Short-term treatment response rates
	1 RCT; 20 people with nodular BCC	People with basal cell nevus syndrome or morpheaform, pigmented and deeply invasive lesions were excluded	High-dose (MPI 5003 0.5 mL [5-FU 15 mg]) v low-dose MPI 5003 0.25 mL [5-FU 7.5 mg]) (high- and low-dose 5-FU given weekly for 4–6 weeks)	3 months	Proportion of lesions with complete histological response: 8/10 (80%) with high dose v 6/10 (60%) with low dose; P = 0.63

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BCC, basal cell carcinoma; 5-FU, 5-fluorouracil.

Table 1.

RCTs of the effects of fluorouracil on cosmesis in people with basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Cosmesis
	1 RCT; 20 people with nodular BCC	People with basal cell nevus syndrome or morpheaform, pigmented and deeply invasive lesions were excluded	High-dose (MPI 5003 0.5 mL [5-FU 15 mg]) v low-dose (MPI 5003 0.25 mL [5-FU 7.5 mg]) fluorouracil	3 months	Cosmetic outcome evaluated by investigators and participants: no significant difference between high dose and low dose: P = 0.34 for physician assessment; P = 0.64 for patient assessment

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BCC, basal cell carcinoma; 5-FU, 5-fluorouracil.

Harms

Fluorouracil versus placebo:

We found no RCTs.

Fluorouracil versus surgery:

We found no RCTs.

Fluorouracil versus cryotherapy:

We found no RCTs.

Fluorouracil versus curettage and cautery/electrodesiccation:

We found no RCTs.

Fluorouracil versus imiquimod 5% cream:

We found no RCTs.

Fluorouracil versus photodynamic therapy:

We found no RCTs.

High-dose versus low-dose fluorouracil:

The additional RCT found that more people given 5-fluorouracil 15 mg than 5-fluorouracil 7.5 mg reported adverse effects, which included transient burning during injection, tenderness and pain, desquamation and erosion, or eschar formation. Treatment-site reactions were more severe in people given 5-fluorouracil 15 mg than 5-fluorouracil 7.5 mg at 2 weeks, but this difference was not significant (significance not assessed: reported as not significant).

Comment

More RCTs are necessary to assess the benefit of 5-fluorouracil for the treatment of BCC.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Cryotherapy/cryosurgery for long-term recurrence

Summary

RECURRENCE Cryotherapy plus curettage compared with surgery: Cryotherapy plus curettage and surgery seem equally effective at reducing recurrence in people with primary nodular or superficial basal cell carcinomas (BCCs) of the head and neck at 5 years ( moderate-quality evidence ). Compared with photodynamic therapy: We don't know whether cryotherapy is more effective at reducing recurrence in people with primary superficial basal cell carcinomas (BCCs) at 2 and 5 years ( very low-quality evidence ). COSMETIC APPEARANCE Compared with photodynamic therapy: Cryotherapy may be less effective at improving cosmetic results in people with superficial or nodular BCCs on the head, neck, legs, and arms at 5 years (very low-quality evidence). NOTE: We found no clinically important results from RCTs about cryotherapy compared with interventions other than photodynamic therapy on recurrence of BCCs at or beyond 2 years after treatment. However, there is consensus that cryotherapy is beneficial for the treatment of BCC.

Benefits

Cryotherapy versus surgery:

We found one systematic review (search date 2006), which identified no RCTs comparing cryotherapy versus surgery for long-term recurrence in people with basal cell carcinoma (BCC).

Cryotherapy plus curettage versus surgery:

See benefits of surgery versus curettage plus cryotherapy.

Cryotherapy versus curettage and cautery/electrodesiccation:

We found no systematic review or RCTs comparing cryotherapy versus curettage and cautery/electrodesiccation.

Cryotherapy versus imiquimod 5% cream:

We found one systematic review (search date 2006), which identified no RCTs comparing cryotherapy versus imiquimod cream.

Cryotherapy versus photodynamic therapy:

We found one systematic review (search date 2006), which identified one RCT comparing cryotherapy versus photodynamic therapy for long-term recurrence in people with BCC. The RCT was reported only in abstract form in two publications, and is therefore not discussed further.

We found one subsequent RCT (118 people with 201 primary superficial BCCs; tumours from all body sites and tumours of diameter 6–15 mm on the face or scalp, less than 20 mm on the extremities or neck and less than 30 mm on the trunk were included) comparing cryotherapy (consisted of two freeze–thaw cycles, each freeze lasting 20 seconds, with a thawing period of 60 seconds) with methyl aminolaevulinic acid photodynamic therapy (MAL-PDT; given once at baseline, as this was prior to European regulatory approval of a 2-treatment regimen) for 3 months. The RCT found no significant differences in recurrence rates between groups at 2 and 5 years after the last treatment (see table 11 ). The recurrence rates in this study were reported as a proportion of the complete responders as opposed to overall cumulative failure rates, thus making the reported P values difficult to interpret.The RCT found that cryotherapy was significantly less effective at improving cosmetic outcomes compared with MAL-PDT at 5 years on investigator assessments, and also on patient assessments (proportion of BCCs assessed as having "excellent" cosmetic outcome by investigators: 16% with cryotherapy v 60% with MAL-PDT; P = 0.00078; significance assessment not performed for patient-assessed outcomes).

Table 1.

RCTs of the effects of interventions on long-term recurrence in people with basal cell carcinoma.

Ref	Population	Characteristics of BCCs	Intervention/comparison	Follow-up	Long-term recurrence
	1 RCT; 118 primary nodular BCCs in 103 people	BCCs at all body sites except mid-face region, orbital areas, and ears. Excluded lesions with a longest diameter of less than 6 mm or greater than 15 mm (face or scalp), greater than 20 mm (extremities or neck), or greater than 30 mm (trunk); and pigmented or morpheaform BCCs	Surgery v photodynamic therapy (MAL-PDT)	2 years	Proportion of lesions with clinical recurrence: 2/52 (4%) with surgery v 10/53 (19%) with MAL-PDT; estimated difference +8, 95% CI –1 to +22
	118 primary nodular BCCs in 103 people	BCCs at all body sites except mid-face region, orbital areas, and ears. Excluded lesions with a longest diameter of less than 6 mm or greater than 15 mm (face or scalp), greater than 20 mm (extremities or neck), or greater than 30 mm (trunk); and pigmented or morpheaform BCCs	Surgery v photodynamic therapy (MAL-PDT)	5 years	Proportion of lesions with clinical recurrence: 2/52 (4%) with surgery v 7/49 (14%) with MAL-PDT; P = 0.09 (per-protocol analysis)
	173 primary nodular BCCs in 149 people	BCCs of less than 2 cm diameter, located anywhere except concave or hair-bearing sites	Surgery v ALA-PDT	2 years	Proportion of people with clinical recurrence: 22% with PDT v 2% with surgery; P value not reported
				3 years	Proportion of people with clinical recurrence: 30% with PDT v 2% with surgery; P less than 0.001
	1 RCT; 408 primary BCCs in 374 people, 204 recurrent facial BCCs in 191 people	BCCs of at least 1 cm in diameter, located in the H zone of the face; included aggressive histological subtype (morpheaform, micronodular BCC with squamous differentiation, trabecular, infiltrative)	Surgery with margin control v MMS	30 months	Proportion of people with clinical recurrence: 5/171 (3%) with surgical excision with margin control v 3/160 (2%) with MMS; RR 0.64, 95% CI 0.16 to 2.64; P = 0.5
	408 primary BCCs in 374 people, 204 recurrent facial BCCs in 191 people	BCCs of at least 1 cm in diameter, located in the H zone of the face; included aggressive histological subtype (morpheaform, micronodular BCC with squamous differentiation, trabecular, infiltrative)	Surgery with margin control v MMS	5 years	Proportion of people with primary BCCs with clinical recurrence: 4% with surgical excision v 2% with MMS; P = 0.397 (percentages estimated from Kaplan-Meier analysis). Proportion of people with recurrent BCCs with clinical recurrence: 12% with surgical excision v 2% with MMS; P = 0.015
	100 primary BCCs in 88 people	BCCs of less than 20 mm diameter of the head and neck. Nodular or superficial histological subtype	Surgery v curettage plus cryotherapy	5 years	Proportion of people with clinical recurrence: 19.6% with curettage plus cryotherapy v 8.4% with surgery; P = 0.1; Hazard ratio 2.57 (95% CI 0.79 to 8.34); recurrence probability calculated from Kaplan-Meier survival analysis
	118 people with 201 primary superficial BCCs	BCCs of any body site; diameter 6–15 mm on face or scalp, less than 20 mm on extremities or neck and less than 30 mm on trunk	Cryotherapy v MAL-PDT	2 years	Proportion of people with clinical recurrence: 24/98 (24%) with cryotherapy v 20/103 (19%) with MAL-PDT; P value not reported
				5 years	Proportion of people with clinical recurrence: 25/98 (26%) with cryotherapy v 25/103 (24%) with MAL-PDT; P value not reported

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BCC, basal cell carcinoma; MAL-PDT, methyl aminolaevulinic acid photodynamic therapy; ALA-PDT, 5-aminolaevulinic acid photodynamic therapy; MMS, Mohs' micrographic surgery

Cryotherapy versus fluorouracil:

We found one systematic review (search date 2006), which identified no RCTs comparing cryotherapy versus fluorouracil.

Harms

Cryotherapy versus surgery:

We found no RCTs.

Cryotherapy plus curettage versus surgery:

See harms of surgery versus curettage plus cryotherapy.

Cryotherapy versus curettage and cautery/electrodesiccation:

We found no RCTs.

Cryotherapy versus imiquimod 5% cream:

We found no RCTs.

Cryotherapy versus photodynamic therapy:

We found one systematic review (search date 2006), which identified one RCT that was reported only in abstract form in two publications, and is therefore not discussed further. The subsequent RCT found minimal difference in the proportion of people reporting adverse effects, although statistical significance was not reported (see table 3 ).

Cryotherapy versus fluorouracil:

We found no RCTs.

Comment

Different regimens of cryotherapy:

Retrospective studies have reported 5-year recurrence rates of 1% with two freeze–thaw cycles of cryotherapy. There is low-quality evidence from a review of cryotherapy that it is an effective treatment for BCC, with cure rates established clinically to be above 90%. Cryotherapy has been used for the treatment of nodular and superficial types of BCC (less than 2 cm size) on the trunk, limbs, head, and neck, including eyelids and ears. For BCCs on the head and neck, surgery is the preferred treatment, with cryotherapy or photodynamic therapy second-line treatments. Curettage and electrodesiccation can also be considered. For treatment of BCCs of the trunk or limbs, surgery, cryotherapy, or photodynamic therapy can be considered. For multiple small superficial BCCs of the trunk and limbs, non-surgical treatments may be preferred because of their reasonable response rates and the impracticality of surgical excision.

Substantive changes

Cryotherapy (recurrence at or beyond 2 years after treatment): One RCT added comparing cryotherapy versus photodynamic therapy. The RCT found no difference between groups in recurrence rates at 2 or 5 years. The RCT also reported that cryotherapy was less effective than photodynamic therapy for investigator- and patient-assessed cosmetic appearance at 5 years. Categorisation unchanged (Likely to be beneficial) based on consensus.

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Curettage and cautery/electrodesiccation for long-term recurrence

Summary

RECURRENCE Curettage plus cryotherapy compared with surgery: Curettage plus cryotherapy and surgery seem equally effective at reducing recurrence in people with primary nodular or superficial basal cell carcinomas (BCCs) of the head and neck at 5 years ( moderate-quality evidence ). NOTE We found no direct information from RCTs about the effects of curettage and cautery/electrodesiccation on recurrence of BCCs at or beyond 2 years after treatment.

Benefits

Curettage and cautery/electrodesiccation alone:

We found no systematic review or RCTs of the effects of curettage and cautery/electrodesiccation alone on long-term recurrence in people with basal cell carcinoma (BCC).

Curettage plus cryotherapy versus surgery:

See benefits of surgery versus curettage plus cryotherapy.

Harms

Curettage and cautery/electrodesiccation alone:

We found no RCTs.

Curettage plus cryotherapy versus surgery:

See harms of surgery versus curettage plus cryotherapy.

Comment

A narrative review of retrospective studies reported 5-year cure rates for BCCs of 82% (for lesions greater than 6 mm in diameter) to 96% (less than 6 mm diameter) for high-risk sites, 77% to 95% for medium-risk sites, and 97% for low-risk BCCs (regardless of size). RCTs are lacking in this area. Curettage and cautery is best suited for treatment of small, low-risk primary nodular or superficial lesions (see comments for cryotherapy).

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Photodynamic therapy for long-term recurrence

Summary

RECURRENCE Compared with surgery: We don't know whether photodynamic therapy is more effective at reducing recurrence of primary nodular basal cell carcinoma (BCC) located anywhere in the body except the central area of the face, orbital areas, and ears at 2 and 5 years ( very low-quality evidence ). Compared with cryotherapy: We don't know whether photodynamic therapy is more effective at reducing recurrence in people with primary superficial BCC at 2 and 5 years ( very low-quality evidence ) COSMETIC APPEARANCE Compared with surgery: Photodynamic therapy using methyl aminolaevulinate cream may be more effective at improving cosmetic results in people with primary nodular BCCs located anywhere on the body except the central area of the face (very low-quality evidence). Compared with cryotherapy: Photodynamic therapy may be more effective at improving cosmetic results in people with superficial or nodular BCCs on the head, neck, legs, and arms at 5 years (very low-quality evidence)

Benefits

Photodynamic therapy versus surgery:

See benefits of surgery versus photodynamic therapy.

Photodynamic therapy versus cryotherapy:

See benefits of cryotherapy versus photodynamic therapy.

Photodynamic therapy versus curettage and cautery/electrodesiccation:

We found no systematic review or RCTs comparing photodynamic therapy versus curettage and cautery/electrodesiccation.

Photodynamic therapy versus imiquimod 5% cream:

We found one systematic review (search date 2006), which identified no RCTs comparing photodynamic therapy versus imiquimod 5% cream.

Photodynamic therapy versus fluorouracil:

We found one systematic review (search date 2006), which identified no RCTs comparing photodynamic therapy versus fluorouracil.

Harms

Photodynamic therapy versus surgery:

See harms of surgery versus photodynamic therapy.

Photodynamic therapy versus cryotherapy:

See harms of cryotherapy versus photodynamic therapy.

Photodynamic therapy versus curettage and cautery/electrodesiccation:

We found no RCTs.

Photodynamic therapy versus imiquimod 5% cream:

We found no RCTs.

Photodynamic therapy versus fluorouracil:

We found no RCTs.

Comment

More long-term studies are needed to assess adequately the effectiveness of photodynamic therapy on long-term recurrence in basal cell carcinoma (see comments for cryotherapy).

Substantive changes

Photodynamic therapy (recurrence at or beyond 2 years after treatment): One RCT added comparing cryotherapy versus photodynamic therapy. The RCT found no difference between groups in recurrence rates at 2 or 5 years. The RCT also reported that photodynamic therapy was more effective than cryotherapy at improving investigator- and patient-assessed cosmetic appearance at 5 years. Categorisation unchanged (Likely to be beneficial) based on consensus.

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Surgery (conventional or Mohs' micrographic surgery) for long-term recurrence

Summary

RECURRENCE Compared with curettage plus cryotherapy: Surgery and curettage plus cryotherapy seem equally effective at reducing recurrence in people with primary nodular or superficial basal cell carcinomas (BCCs) of the head and neck at 5 years ( moderate-quality evidence ). Compared with photodynamic therapy: We don't know whether surgery is more effective at reducing recurrence of primary nodular BCC located anywhere in the body except the central area of the face, orbital areas, and ears at 2 and 5 years ( very low-quality evidence ). Different types of surgery compared with each other: We don't know whether surgery with margin control is more effective than Mohs' micrographic surgery (MMS) at reducing the rate of clinical recurrence of primary BCCs at 30 months and 5 years; however, surgery with margin control may be more effective at reducing the rate of clinical recurrence for recurrent BCCs at 5 years ( low-quality evidence ). COSMETIC APPEARANCE Compared with photodynamic therapy: Surgery may be less effective at improving cosmetic results in people with primary nodular BCCs located anywhere in the body except the central area of the face, orbital areas, and ears (very low-quality evidence). Different types of surgery compared with each other: We don't know whether surgery with margin control is more effective than MMS at improving cosmetic results of BCCs at 18 months (very low-quality evidence). ADVERSE EFFECTS Surgical excision for recurrent BCCs causes more complications compared with MMS.

Benefits

Surgery versus cryotherapy:

See benefits of cryotherapy versus surgery.

Surgery versus curettage plus cryotherapy:

We found one RCT (88 people with primary nodular or superficial BCCs of the head and neck) comparing surgery versus curettage plus cryotherapy at 5 years. Tumours measured less than 20 mm in clinical diameter, and surgical excision margins were at least 3 mm. People randomised to receive curettage and cryotherapy had curettage of the lesion followed by cryotherapy, which consisted of two freeze-thaw cycles (each freeze lasting 20 seconds, with a thawing period of 60 seconds). The RCT found no significant difference in the rate of recurrence with surgery compared with curettage plus cryotherapy at 5 years (see table 11 ).

Surgery versus curettage and cautery/electrodesiccation:

We found no systematic review, RCTs, or cohort studies comparing surgery versus curettage and cautery/electrodesiccation.

Surgery versus imiquimod 5% cream:

We found one systematic review (search date 2006), which identified no RCTs comparing surgery versus imiquimod 5% cream.

Surgery versus photodynamic therapy:

We found one systematic review (search date 2006), which identified one RCT (118 primary nodular BCCs in 103 people) comparing surgery versus photodynamic therapy using methyl aminolaevulinate cream (MAL-PDT) for long-term recurrence in people with BCC. Surgical excision margins were at least 5 mm. MAL-PDT was given twice, 1 week apart. BCCs that had not completely disappeared on clinical inspection 3 months after initial MAL-PDT were given a second cycle of MAL-PDT. The review did not report on recurrence at 2 years; however, the RCT included in the review did report this outcome. It found a lower recurrence rate (assessed clinically) at 2 years with surgery compared with MAL-PDT for primary nodular BCCs located anywhere in the body except the central area of the face (see table 11 ). However, the difference between the groups did not reach statistical significance. The authors commented that the RCT was not powered to assess long-term recurrence rates. We also found a long-term follow-up of this RCT, which found no significant differences for recurrence rates between groups at 5 years (see table 11 ). Cosmetic outcome was assessed by investigators and participants at 3, 12, and 24 months after surgery or last MAL-PDT treatment. The RCT did not state if investigators were blinded to treatment when assessing cosmetic outcome. The RCT found that, compared with surgical excision, MAL-PDT significantly improved cosmetic outcome at 24 months on both investigator and participant assessment (see table 11 ). Only per-protocol analysis was reported.

We found one subsequent RCT (173 primary nodular BCCs in 149 people) comparing surgery versus 5-aminolaevulinic acid photodynamic therapy (ALA-PDT). Surgical excision margins were at least 3 mm. People randomised to receive ALA-PDT had tumour debulking by curette, 3 weeks prior to the ALA-PDT treatment. The RCT found that surgery reduced the rate of recurrence at 2 years compared with ALA-PDT (statistical significance not reported) (see table 11 ). After 3 years' follow-up, the RCT found that surgery significantly reduced the rate of recurrence compared with ALA-PDT.

Surgery versus fluorouracil:

We found one systematic review (search date 2006), which identified no RCTs comparing surgery versus fluorouracil.

Different types of surgery versus each other:

We found one systematic review (search date 2006), which identified one RCT (408 primary facial BCCs in 374 people; 204 recurrent facial BCCs in 191 people) comparing surgery versus Mohs' micrographic surgery (MMS). The RCT reported results for primary and recurrent BCCs separately. The review found no significant difference in the rate of clinical recurrence of primary BCCs at 2.5 years between surgical excision with a 3-mm margin and MMS (see table 11 ). Recurrence at 30 months was not reported for recurrent facial BCCs. The study included histologically confirmed BCCs of at least 1 cm in diameter, located in the high-risk H zone of the face, or an aggressive histological subtype. If the resection margins were positive after surgical excision, a re-excision with a 3-mm margin was done, and if the margins remained positive after re-excision, MMS was performed. In the surgical-excision group, the number of people in whom the defect was immediately reconstructed or left open awaiting histopathology results after surgical excision was unclear. Failure to take this factor into account when analysing the results could introduce bias in favour of surgery with margin control. The result of the RCT cannot be generalised to simple surgical excision without margin control. Cosmetic results were assessed by participants, and by three professionals and three lay people, using photographs. The RCT did not state whether investigators were blinded to treatment when assessing cosmetic outcome. The RCT found no significant difference in cosmetic outcome 18 months after treatment between surgical excision and MMS (absolute numbers and P value not reported). It found that cosmetic results became significantly worse with increasing defect size for primary and recurrent BCCs (P less than 0.001). However, there was no significant difference between surgical excision and MMS in the mean defect size for primary or recurrent BCCs (see table 8 ).

We found one long-term follow-up report with 5-year data for the RCT included in the review. The follow-up study found no significant difference in the rate of clinical recurrences of primary BCCs between surgical excision with a 3-mm margin and MMS at 5 years. However, for recurrent BCCs, the study found that MMS significantly reduced recurrence rate at 5 years compared with surgical excision (see table 11 ).

Harms

Surgery versus cryotherapy:

See harms of cryotherapy versus surgery.

Surgery versus curettage plus cryotherapy:

The RCT found a slightly higher proportion of people having surgical excision required systemic antibiotics for wound infection, but the statistical significance of these results was not reported (see table 3 ).

Surgery versus curettage and cautery/electrodesiccation:

We found no RCTs.

Surgery versus imiquimod 5% cream:

We found no RCTs.

Surgery versus photodynamic therapy:

The review found that surgery significantly reduced the proportion of people with any adverse effects compared with MAL-PDT (see table 3 ). The RCT identified by the review found that more people reported transient local reactions — such as burning sensation of the skin, pain in the skin, or erythema — with MAL-PDT compared with surgery, but significance values for these adverse effects were not reported (see table 3 ). The subsequent RCT reported no significant difference in the proportion of people with secondary wound infection (see table 3 ).

Surgery versus fluorouracil:

We found no RCTs.

Different types of surgery versus each other:

The RCT identified by the review found no difference in postoperative adverse events between surgery and MMS for primary BCCs. Long-term follow-up of the RCT reported significantly more adverse events — including wound infections, graft necrosis, postoperative bleeding, or a combination — after surgery than after MMS for recurrent BCCs (see table 3 ).

Comment

The RCT comparing surgical excision with margin control versus MMS found that 35/199 (18%) primary BCCs and 32/102 (32%) recurrent BCCs were incompletely excised on first surgical excision. Primary tumours with aggressive histology were significantly more likely to be incompletely excised than those of the non-aggressive type (P = 0.022). MMS may be more effective for the treatment of aggressive BCCs than excisional surgery. There is limited evidence that surgery is associated with: better cosmetic results compared with cryotherapy, similar cosmetic results compared with MMS, and worse cosmetic results compared with photodynamic therapy (see comments for cryotherapy).

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Fluorouracil for long-term recurrence

Summary

We found no direct information from RCTs about the effects of fluorouracil on recurrence of basal cell carcinoma at or beyond 2 years after treatment.

Benefits

We found one systematic review (search date 2006), which identified no RCTs of the effects of fluorouracil on long-term recurrence in people with basal cell carcinoma.

Harms

We found no RCTs.

Comment

Longer-term studies are needed to adequately assess the effectiveness of fluorouracil on long-term recurrence in basal cell carcinoma.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Apr 6;2010:1719.

Imiquimod 5% cream for long-term recurrence

Summary

We found no direct information from RCTs about the effects of imiquimod 5% cream on recurrence of basal cell carcinomas at or beyond 2 years after treatment.

Benefits

We found one systematic review (search date 2006), which identified no RCTs of the effects of imiquimod 5% cream on long-term recurrence in people with basal cell carcinoma.

Harms

We found no RCTs.

Comment

Longer-term studies are needed to adequately assess the effect of imiquimod 5% cream on long-term recurrence in basal cell carcinoma.

Substantive changes

No new evidence

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PERMALINK

Basal cell carcinoma

Anthony Ormerod

Sanjay Rajpara

Fiona Craig, MBBS, MRCP

Roles

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

About this condition

Definition

Incidence/ Prevalence

Aetiology/ Risk factors

Prognosis

Aims of intervention

Outcomes

Methods

Table 1.

Glossary

Disclaimer

Contributor Information

References

Cryotherapy/cryosurgery for short-term treatment response

Summary

Benefits

Cryotherapy alone versus surgery:

Cryotherapy plus curettage versus surgery:

Cryotherapy versus curettage and cautery/electrodesiccation:

Cryotherapy versus imiquimod 5% cream:

Cryotherapy versus photodynamic therapy:

Table 1.

Table 1.

Cryotherapy versus fluorouracil:

Harms

Cryotherapy alone versus surgery:

Cryotherapy plus curettage versus surgery:

Cryotherapy versus curettage and cautery/electrodesiccation:

Cryotherapy versus imiquimod 5% cream:

Cryotherapy versus photodynamic therapy:

Table 1.

Cryotherapy versus fluorouracil:

Comment

Substantive changes

Curettage and cautery/electrodesiccation for short-term treatment response

Summary

Benefits

Curettage and cautery/electrodesiccation alone versus surgery:

Curettage plus cryotherapy versus surgery:

Curettage and cautery/electrodesiccation versus cryotherapy:

Curettage and cautery/electrodesiccation versus imiquimod 5% cream:

Curettage and cautery/electrodesiccation versus photodynamic therapy:

Curettage and cautery/electrodesiccation versus fluorouracil:

Different regimens of curettage and cautery/electrodesiccation versus each other:

Harms

Curettage and cautery/electrodesiccation alone versus surgery:

Curettage plus cryotherapy versus surgery:

Curettage and cautery/electrodesiccation versus cryotherapy:

Curettage and cautery/electrodesiccation versus imiquimod 5% cream:

Curettage and cautery/electrodesiccation versus photodynamic therapy:

Curettage and cautery/electrodesiccation versus fluorouracil:

Different regimens of curettage and cautery/electrodesiccation versus each other:

Comment

Substantive changes

Imiquimod 5% cream for short-term treatment response

Summary

Benefits

Imiquimod 5% cream versus placebo:

Table 1.

Imiquimod 5% cream versus surgery:

Imiquimod 5% cream versus cryotherapy:

Imiquimod 5% cream versus curettage and cautery/electrodesiccation:

Imiquimod 5% cream plus curettage and electrodesiccation versus placebo plus curettage and electrodesiccation:

Imiquimod 5% cream versus photodynamic therapy:

Imiquimod 5% cream versus fluorouracil:

Different dosing regimens of imiquimod 5% cream versus each other:

Imiquimod 5% cream with occlusion versus imiquimod 5% cream without occlusion:

Harms