Skin disorders. Basal cell carcinoma December 2009 Anthony Ormerod, Sanjay Rajpara, and Fiona Craig ...

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1 December 29 Anthony Ormerod, Sanjay Rajpara, and Fiona Craig ABSTRACT INTRODUCTION: (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 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 29 (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). 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? TREATMENT RESPONSE IN BASAL CELL CARCINO- MA Likely to be beneficial Cryotherapy/cryosurgery (as effective as photodynamic therapy; in combination with curettage seems to be as effective as excisional surgery) Curettage and cautery/electrodesiccation (likely to be beneficial for low-risk BCC)* Imiquimod 5% cream (better than placebo at 6 months, insufficient evidence to compare with other treatments) Photodynamic therapy Surgery (excisional or Mohs' micrographic surgery)* Unknown effectiveness Fluorouracil LONG-TERM RECURRENCE IN BASAL CELL CAR- CINOMA Likely to be beneficial Cryotherapy/cryosurgery* Key points INTERVENTIONS Curettage and cautery/electrodesiccation* Photodynamic therapy* Surgery (conventional or Mohs' micrographic surgery) Unknown effectiveness Fluorouracil Imiquimod 5% cream To be covered in future updates Radiotherapy Footnote *Categorisation is based on consensus and expert opinion. Categorisation is based on consensus and observational data. (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 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. BMJ Publishing Group Ltd 21. All rights reserved Clinical Evidence 21;:1719

2 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). DEFINITION (BCC) is the most common cancer found in humans. [1] 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. [2] Most BCCs (85%) develop on the head and neck. [3] [] 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. [2] INCIDENCE/ PREVALENCE The reported incidence of BCC varies in the literature. The incidence was reported to be 788 per 1, population per year in 1995 in Australia, [5] and 16 per 1, population per year in 199 in the USA. [6] A Dutch study reported an incidence of 2 per 1, population per year, [7] whereas the incidence in the UK is reported to be lower, at about 1 cases per 1, population per year. [8] Because of incomplete registration of cases, some of these estimates may be low. The incidence of BCC increases markedly after the age of years, and the incidence in younger people is increasing, possibly as a result of increased sun exposure. [1] AETIOLOGY/ The reported risk factors for developing BCC include fair skin, tendency to freckle, [9] degree of RISK FACTORS sun exposure, [1] [11] [12] excessive sun-bed use, smoking, radiotherapy, phototherapy, male gender, and a genetic predisposition. [13] 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. [13] 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 1-fold increased risk compared with the general population. [1] An autosomal-dominant condition, naevoid BCC syndrome (Gorlin's syndrome) is characterised by the occurrence of multiple BCCs and developmental abnormalities. [1] PROGNOSIS The following factors can affect prognosis: tumour size, site, type, growth pattern/histological subtype, failure of previous treatment (recurrence), and immunosuppression. [2] 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- BMJ Publishing Group Ltd 21. All rights reserved

3 labial fold, eyelids and periorbital areas, lips, chin, and ears); medium risk (scalp, forehead, preand postauricular areas, and malar areas); and low risk (neck, trunk, and extremities). [15] Histologically, micronodular, infiltrative, morphoeic, and basosquamous types of BCC are classed as high risk. [16] Distant metastases are rare. [17] Although some BCCs tend to infiltrate tissues in a threedimensional 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. [1] AIMS OF Prevention of recurrence, complete excision, complete histological and clinical response, good INTERVENTION cosmetic result, avoidance of adverse effects of treatment. OUTCOMES METHODS QUESTION 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. Clinical Evidence search and appraisal December 29. The following databases were used to identify studies for this systematic review: Medline 1966 to December 29, Embase 198 to December 29, and The Cochrane Library (all databases), issue, 29. 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 2 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 29) 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 ( We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 32 ). What are the effects of interventions on treatment response/recurrence (within 1 year of therapy) in people with basal cell carcinoma? OPTION CRYOTHERAPY/CRYOSURGERY FOR SHORT-TERM TREATMENT RESPONSE 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 BMJ Publishing Group Ltd 21. All rights reserved.... 3

4 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). For GRADE evaluation of interventions for basal cell carcinoma, see table, p 32. 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, p 11. 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 26), which identified no RCTs comparing cryotherapy versus imiquimod cream. [1] Cryotherapy versus photodynamic therapy: We found one systematic review (search date 26), [1] 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. [18] [19] 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, p 23 ). [2] There was also no significant difference in clinical response rates at 1 year between photodynamic therapy and cryotherapy (see table 1, p 23 ). Cryotherapy consisted of two freeze thaw cycles (each freeze lasting 25 3 seconds, with a thawing period of 2 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 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/ (3%) lesions in the ALA-PDT group were retreated compared with 1/39 (3%) in the cryotherapy group. [2] 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, p 23 ). [2] We found one subsequent RCT (118 people with 21 primary superficial BCCs; tumours from all body sites and tumours of diameter 6 15 mm on the face or scalp, less than 2 mm on the extremities or neck, and less than 3 mm on the trunk were included) comparing cryotherapy (consisting of 2 freeze thaw cycles, each freeze lasting 2 seconds, with a thawing period of 6 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. [21] 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, p 23 ). 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, p 23 ). [21] Cryotherapy versus fluorouracil: We found one systematic review (search date 26), which identified no RCTs comparing cryotherapy versus fluorouracil. [1] BMJ Publishing Group Ltd 21. All rights reserved....

5 Harms: Comment: OPTION Cryotherapy alone versus surgery: Cryotherapy plus curettage versus surgery: See harms of surgery (conventional or Mohs' micrographic surgery) for short-term treatment response, p 11. Cryotherapy versus curettage and cautery/electrodesiccation: Cryotherapy versus imiquimod 5% cream: 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, p 2 ). [1] There was a significantly shorter healing time after ALA-PDT compared with cryotherapy (absolute numbers not reported; P less than.1). [2] The subsequent RCT found minimal difference in the proportion of people reporting adverse effects, although statistical significance was not reported (see table 3, p 2 ). [21] Cryotherapy versus fluorouracil: 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. [1] However, in a study primarily looking at cosmetic outcome, cryotherapy had a failure rate of 7% (3/8) compared with % failure rate for surgery for head and neck tumours. [7] 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. CURETTAGE AND CAUTERY/ELECTRODESICCATION FOR SHORT-TERM TREATMENT RESPONSE 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. For GRADE evaluation of interventions for basal cell carcinoma, see table, p 32. BMJ Publishing Group Ltd 21. All rights reserved.... 5

6 Benefits: Harms: Comment: 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, p 11. 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, p 7. 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 1 people) comparing one session of C&D versus three sessions of C&D. [22] 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 [5%] 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). Curettage and cautery/electrodesiccation alone versus surgery: Curettage plus cryotherapy versus surgery: See harms of surgery (conventional or Mohs' micrographic surgery) for short-term treatment response, p 11. Curettage and cautery/electrodesiccation versus cryotherapy: 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, p 7. Curettage and cautery/electrodesiccation versus photodynamic therapy: Curettage and cautery/electrodesiccation versus fluorouracil: Different regimens of curettage and cautery/electrodesiccation versus each other: The RCT gave no information about adverse effects. [22] 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 3% 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%. [15] BMJ Publishing Group Ltd 21. All rights reserved.... 6

7 OPTION IMIQUIMOD 5% CREAM FOR SHORT-TERM TREATMENT RESPONSE Treatment response Compared with placebo Imiquimod 5% cream applied for between 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. For GRADE evaluation of interventions for basal cell carcinoma, see table, p 32. Benefits: Imiquimod 5% cream versus placebo: We found one systematic review with meta-analysis (search date 26; 5 RCTs; 115 people with superficial or nodular basal cell carcinomas [BCCs]) comparing imiquimod 5% cream versus placebo (vehicle cream). [1] 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, p 26 ). We found one additional RCT (72 people with nodular, superficial, or mixed BCCs) comparing different regimens of imiquimod 5% versus placebo. [23] Imiquimod 5% or placebo was applied 5 days a week for 2,, 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, p 26 ). [23] It found that imiquimod 5% given for or 6 weeks significantly improved the complete response rate compared with placebo (see table, p 26 ). [23] 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. [2] Each topical treatment was applied nightly under occlusion. MMS was performed 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, p 26 ). [2] Imiquimod 5% cream versus surgery: We found one systematic review (search date 26), which identified no RCTs comparing imiquimod 5% cream versus surgery. [1] Imiquimod 5% cream versus cryotherapy: We found one systematic review (search date 26), which identified no RCTs comparing imiquimod 5% cream versus cryotherapy. [1] BMJ Publishing Group Ltd 21. All rights reserved.... 7

8 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 (2 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. [25] The RCT found that adding imiquimod 5% treatment to C&D increased histological tumour clearance at 8 weeks (P value not reported; see table, p 26 ).The RCT found no significant difference between the groups in cosmetic appearance at 8 weeks using the Vancouver scale (mean Vancouver scale score:.5 with imiquimod plus C&D v.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. [25] Imiquimod 5% cream versus photodynamic therapy: We found one systematic review (search date 26), which identified no RCTs comparing imiquimod 5% cream versus photodynamic therapy. [1] Imiquimod 5% cream versus fluorouracil: We found one systematic review (search date 26), which identified no RCTs comparing imiquimod 5% cream versus fluorouracil. [1] Different dosing regimens of imiquimod 5% cream versus each other: We found one systematic review with meta-analysis (search date 26; 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. [1] 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, p 26 ). [1] Another RCT identified by the review but not included in the metaanalysis (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. [26] 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, p 26 ). [26] 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). [27] The RCT found no significant difference in tumour clearance between the two regimens at 19 weeks (see table, p 26 ). 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). [27] Treatment response was assessed clinically but not histologically, which could be seen as a possible weakness of this study. [27] Imiquimod 5% cream with occlusion versus imiquimod 5% cream without occlusion: We found one systematic review (search date 26), which identified two RCTs comparing imiquimod 5% cream with occlusion versus imiquimod 5% cream without occlusion. [1] Both RCTs were reported in the same article. [26] The first RCT enrolled 93 people with superficial BCC, and the second RCT enrolled 9 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, p 26 ). [1] 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. [1] 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, p 2 ). [23] 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, p 2 ). [2] Imiquimod 5% cream versus surgery: BMJ Publishing Group Ltd 21. All rights reserved.... 8

9 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: The RCT found that fewer people given imiquimod 5% plus C&D had healed at weeks compared with placebo plus C&D (% with imiquimod plus C&D v 1% with placebo plus C&D alone; P value not reported). At 8 weeks, all excision sites were healed. [25] Imiquimod 5% cream versus photodynamic therapy: Imiquimod 5% cream versus fluorouracil: 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. [1] The additional RCT found similar rates of application site reactions with both regimens. [27] 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, p 2 ). [27] 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). [1] 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 1% with five applications a week or more treatment with the imiquimod 5% cream for superficial and nodular BCCs. [1] [23] [25] [26] There is no good evidence that imiquimod is a useful adjunct to Mohs' micrographic surgery. [2] OPTION PHOTODYNAMIC THERAPY FOR SHORT-TERM TREATMENT RESPONSE 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). BMJ Publishing Group Ltd 21. All rights reserved.... 9

10 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. For GRADE evaluation of interventions for basal cell carcinoma, see table, p 32. Benefits: Photodynamic therapy versus placebo: We found one systematic review (search date 26), [1] which identified two RCTs comparing photodynamic therapy versus placebo for treatment response in people with basal cell carcinoma (BCC). [28] [29] 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, p 3. Photodynamic therapy versus surgery: See benefits of surgery versus photodynamic therapy, p 11. 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 26), which identified no RCTs comparing photodynamic therapy versus imiquimod 5% cream. [1] Photodynamic therapy versus fluorouracil: We found one systematic review (search date 26), which identified no RCTs comparing photodynamic therapy versus fluorouracil. [1] Different types of photodynamic therapy versus each other: We found one systematic review (search date 26), [1] which identified two RCTs [3] [31] of the effects of different types of photodynamic therapy on treatment response and cosmetic outcome. We found two additional RCTs. [32] [33] The first RCT [3] identified by the review [1] assessed nonmelanoma 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 25 superficial BCCs) [31] identified by the review [1] 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, p 27 ). [31] All people received 15 minutes of local pretreatment with 99% dimethyl sulfoxide, followed by topical application of 2% 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 laserlight ALA-PDT and broadband-lamp light ALA-PDT (see table 6, p 27 ). [1] The first additional RCT compared ALA-PDT using single illumination versus fractionated twofold illumination. [32] 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, p 27 ). People in the single-illumination group received a light fraction of 75 J/cm 2, whereas those in the twofold-illumination group received light fractions of 2 and 8 J/cm 2 at and 6 hours after the ALA. [32] 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 3 nodular BCCs) compared two cycles of ALA-PDT versus two cycles of methyl aminolaevulinic acid photodynamic therapy (MAL-PDT). [33] The RCT found no significant difference in histological response to treatment at 8 weeks between ALA-PDT and MAL-PDT (see table 5, p 27 ). [33] BMJ Publishing Group Ltd 21. All rights reserved.... 1

11 Harms: Comment: OPTION Photodynamic therapy versus placebo: The RCTs identified by the systematic review were reported in abstract form only and are therefore [28] [29] not discussed further. Photodynamic therapy versus cryotherapy: See harms of cryotherapy versus photodynamic therapy, p 3. Photodynamic therapy versus surgery: See harms of surgery versus photodynamic therapy, p 11. Photodynamic therapy versus curettage and cautery/electrodesiccation: Photodynamic therapy versus imiquimod 5% cream: Photodynamic therapy versus fluorouracil: 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, p 2 ). [31] During the first week after treatment, 68% of people in the laser-light ALA-PDT group and 7% 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). [31] The first additional RCT found that more people given twofold illumination than single illumination required pain relief during or after treatment (see table 3, p 2 ). [32] The second additional RCT found no significant difference in the intensity of pain during illumination between ALA-PDT and MAL-PDT (see table 3, p 2 ). [33] 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. SURGERY (EXCISIONAL OR MOHS' MICROGRAPHIC SURGERY) FOR SHORT-TERM TREATMENT RESPONSE Treatment response Compared with curettage plus cryotherapy We don't know whether surgery is more effective at reducing treatmentfailure 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 lowquality 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 BMJ Publishing Group Ltd 21. All rights reserved

12 Surgical excision is associated with more adverse effects compared with Mohs' micrographic surgery but less than photodynamic therapy. For GRADE evaluation of interventions for basal cell carcinoma, see table, p 32. 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 26), [1] which identified one RCT (96 primary superficial or nodular basal cell carcinomas [BCCs]) [7] 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 2 seconds, with a thawing period of 6 seconds). The review found no significant difference in clinical treatment-failure rates at 1 year between surgery and curettage plus cryotherapy (see table 7, p 28 ). 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. [7] 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, p 29 ). However, the difference for participant assessment was not significant (P =.15). [7] It found no significant difference in cosmetic outcome judged by a beautician between surgery and curettage plus cryotherapy (see table 8, p 29 ). 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 26), which identified no RCTs comparing surgery versus imiquimod cream. [1] Surgery versus photodynamic therapy: We found one systematic review (search date 26), [1] which identified one RCT, [36] and two subsequent RCTs. [3] [35] The RCT (118 primary nodular BCCs in 13 people) compared surgical excision versus photodynamic therapy using methyl aminolaevulinate cream (MAL-PDT). [36] 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 2 mm for the extremities or neck, or more than 3 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, p 28 ). [1] 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 2 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, p 29 ). [36] Only per-protocol analysis was reported. [36] The first subsequent RCT (19 people with 173 nodular BCCs of 2 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). [3] 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, p 28 ), but at 1 year, surgery significantly reduced the risk of recurrence compared with ALA-PDT (see table 7, p 28 ). The risk of recurrence after PDT was significantly increased in tumours with a maximum thickness of 1.3 mm or more (2% failure rate v 16% in tumours less than 1.3 mm thick; absolute numbers not reported). This RCT did not report cosmetic outcomes. [3] BMJ Publishing Group Ltd 21. All rights reserved