Interventions for basal cell carcinoma of the skin
Basal cell carcinoma (BCC) is the commonest cancer affecting white‐skinned individuals, and worldwide incidence is increasing. Although rarely fatal, BCC is associated with significant morbidity and costs. First‐line treatment is usually surgical excision, but alternatives are available. New published studies and the development of non‐surgical treatments meant an update of our Cochrane Review (first published in 2003, and previously updated in 2007) was timely.
To assess the effects of interventions for BCC in immunocompetent adults.
We updated our searches of the following databases to November 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and LILACS.
Randomised controlled trials (RCTs) of interventions for BCC in immunocompetent adults with histologically‐proven, primary BCC. Eligible comparators were placebo, active treatment, other treatments, or no treatment.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. Primary outcome measures were recurrence at three years and five years (measured clinically) (we included recurrence data outside of these time points if there was no measurement at three or five years) and participant‐ and observer‐rated good/excellent cosmetic outcome. Secondary outcomes included pain during and after treatment, early treatment failure within six months, and adverse effects (AEs). We used GRADE to assess evidence certainty for each outcome.
We included 52 RCTs (26 new) involving 6690 participants (median 89) in this update. All studies recruited from secondary care outpatient clinics. More males than females were included. Study duration ranged from six weeks to 10 years (average 13 months). Most studies (48/52) included only low‐risk BCC (superficial (sBCC) and nodular (nBCC) histological subtypes). The majority of studies were at low or unclear risk of bias for most domains. Twenty‐two studies were industry‐funded: commercial sponsors conducted most of the studies assessing imiquimod, and just under half of the photodynamic therapy (PDT) studies.
Overall, surgical interventions have the lowest recurrence rates. For high‐risk facial BCC (high‐risk histological subtype or located in the facial 'H‐zone' or both), there may be slightly fewer recurrences with Mohs micrographic surgery (MMS) compared to surgical excision (SE) at three years (1.9% versus 2.9%, respectively) (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.16 to 2.64; 1 study, 331 participants; low‐certainty evidence) and at five years (3.2% versus 5.2%, respectively) (RR 0.61, 95% CI 0.18 to 2.04; 1 study, 259 participants; low‐certainty evidence). However, the 95% CI also includes the possibility of increased risk of recurrence and no difference between treatments. There may be little to no difference regarding improvement of cosmetic outcomes between MMS and SE, judged by participants and observers 18 months post‐operatively (one study; low‐certainty evidence); however, no raw data were available for this outcome.
When comparing imiquimod and SE for nBCC or sBCC at low‐risk sites, imiquimod probably results in more recurrences than SE at three years (16.4% versus 1.6%, respectively) (RR 10.30, 95% CI 3.22 to 32.94; 1 study, 401 participants; moderate‐certainty evidence) and five years (17.5% versus 2.3%, respectively) (RR 7.73, 95% CI 2.81 to 21.3; 1 study, 383 participants; moderate‐certainty evidence). There may be little to no difference in the number of participant‐rated good/excellent cosmetic outcomes (RR 1.00, 95% CI 0.94 to 1.06; 1 study, 326 participants; low‐certainty evidence). However, imiquimod may result in greater numbers of good/excellent cosmetic outcomes compared to SE when observer‐rated (60.6% versus 35.6%, respectively) (RR 1.70, 95% CI 1.35 to 2.15; 1 study, 344 participants; low‐certainty evidence). Both cosmetic outcomes were measured at three years.
Based on one study of 347 participants with high‐ and low‐risk primary BCC of the face, radiotherapy may result in more recurrences compared to SE under frozen section margin control at three years (5.2% versus 0%, respectively) (RR 19.11, 95% CI 1.12 to 325.78; low‐certainty evidence) and at four years (6.4% versus 0.6%, respectively) (RR 11.06, 95% CI 1.44 to 84.77; low‐certainty evidence). Radiotherapy probably results in a smaller number of participant‐ (RR 0.76, 95% CI 0.63 to 0.91; 50.3% versus 66.1%, respectively) or observer‐rated (RR 0.48, 95% CI 0.37 to 0.62; 28.9% versus 60.3%, respectively) good/excellent cosmetic outcomes compared to SE, when measured at four years, where dyspigmentation and telangiectasia can occur (both moderate‐certainty evidence).
Methyl‐aminolevulinate (MAL)‐PDT may result in more recurrences compared to SE at three years (36.4% versus 0%, respectively) (RR 26.47, 95% CI 1.63 to 429.92; 1 study; 68 participants with low‐risk nBCC in the head and neck area; low‐certainty evidence). There were no useable data for measurement at five years. MAL‐PDT probably results in greater numbers of participant‐ (RR 1.18, 95% CI 1.09 to 1.27; 97.3% versus 82.5%) or observer‐rated (RR 1.87, 95% CI 1.54 to 2.26; 87.1% versus 46.6%) good/excellent cosmetic outcomes at one year compared to SE (2 studies, 309 participants with low‐risk nBCC and sBCC; moderate‐certainty evidence).
Based on moderate‐certainty evidence (single low‐risk sBCC), imiquimod probably results in fewer recurrences at three years compared to MAL‐PDT (22.8% versus 51.6%, respectively) (RR 0.44, 95% CI 0.32 to 0.62; 277 participants) and five years (28.6% versus 68.6%, respectively) (RR 0.42, 95% CI 0.31 to 0.57; 228 participants). There is probably little to no difference in numbers of observer‐rated good/excellent cosmetic outcomes at one year (RR 0.98, 95% CI 0.84 to 1.16; 370 participants). Participant‐rated cosmetic outcomes were not measured for this comparison.
AEs with surgical interventions include wound infections, graft necrosis and post‐operative bleeding. Local AEs such as itching, weeping, pain and redness occur frequently with non‐surgical interventions. Treatment‐related AEs resulting in study modification or withdrawal occurred with imiquimod and MAL‐PDT.
Surgical interventions have the lowest recurrence rates, and there may be slightly fewer recurrences with MMS over SE for high‐risk facial primary BCC (low‐certainty evidence). Non‐surgical treatments, when used for low‐risk BCC, are less effective than surgical treatments, but recurrence rates are acceptable and cosmetic outcomes are probably superior. Of the non‐surgical treatments, imiquimod has the best evidence to support its efficacy.
Overall, evidence certainty was low to moderate. Priorities for future research include core outcome measures and studies with longer‐term follow‐up.
Jason Thomson, Sarah Hogan, Jo Leonardi-Bee, Hywel C Williams, Fiona J Bath-Hextall
Plain language summary
Interventions for basal cell carcinoma of the skin
Why is this question important?
Basal cell carcinoma (BCC) is the most common form of skin cancer among people with white skin.
BCC is not usually life‐threatening but if left untreated, it can cause important disfigurement, especially on the face.
Surgical removal of the affected area and surrounding skin is usually the first option for treating BCC. Several different surgical approaches exist as well as non‐surgical treatments, such as radiotherapy (high doses of radiation that kill cancer cells), and anti‐cancer creams, gels and ointments.
We reviewed the evidence from research studies, to find out which treatments work best for BCC.
How did we identify and evaluate the evidence?
We searched for randomised controlled studies (studies where people are randomly put into one of two or more treatment groups), because these provide the most robust evidence about the effects of a treatment. We compared and summarised the evidence from all the studies. Finally, we rated our confidence in the evidence, based on factors such as study methods and sizes, and the consistency of findings across studies.
What did we find?
We found 52 studies that involved a total of 6690 adults with BCC. Most studies (48 out of 52) included hospital outpatients with small, superficial or nodular BCC. Studies lasted for between six weeks and 10 years (average duration: 13 months). Twenty‐two studies were funded by pharmaceutical companies.
Our confidence in the evidence presented here is low to moderate, mainly because many studies were small.
Comparison between different surgical treatments
‐ Mohs micrographic surgery (a specialised surgical approach that removes less skin) may slightly decrease recurrence rates at three and five years compared to surgical excision (one of the most common surgical treatments for BCC).
‐There may be little to no difference in how well scars heal between these two surgical treatments according to patients and observers (one study).
Surgery versus non‐surgical treatments
Compared against surgical excision:
‐ Imiquimod (an anti‐cancer cream) probably increases BCC recurrence rates at three and five years. There may be little to no difference in scar healing according to patients, although imiquimod may increase chances of scars healing well when healing is rated by an observer (one study).-‐ Radiotherapy may increase BCC recurrence rates at three and four years, and probably decreases chances of scars healing well (one study).-‐ MAL‐PDT, a type of photodynamic therapy (that uses a light source and light‐sensitive medicine to kill cancer cells), may increase BCC recurrence rates at three years. MAL‐PDT probably increases chances of scars healing well (two studies).
Comparison of different non‐surgical treatments
Compared against imiquimod:
‐ MAL‐PDT probably increases BCC recurrence rates at three and five years. There is probably little to no difference in scar healing (one study);
What does this mean?
Overall, the evidence suggests that:
‐ surgery could reduce chances of BCC recurrence;-‐ non‐surgical treatments such as anti‐cancer creams or photodynamic therapy carry an increased chance of BCC recurrence, but could increase chances of scars healing well compared with surgery.
Complications with surgical treatments include wound infections, skin graft failure and bleeding after the procedure. Non‐surgical treatments frequently lead to localised itching, weeping, pain and redness. Treatment‐related side effects that caused modifications to the study or the withdrawal of participants occurred with imiquimod and MAL‐PDT.
How‐up‐to date is this review?
The evidence in this Cochrane Review is current to November 2019.
Jason Thomson, Sarah Hogan, Jo Leonardi-Bee, Hywel C Williams, Fiona J Bath-Hextall
Implications for practice
The overall quality of research on interventions for basal cell carcinoma (BCC) has improved since our 2007 review with the publication of several randomised controlled trials (RCTs) with long‐term follow‐up, but many of the included studies have provided low‐ or moderate‐certainty evidence that should be interpreted with caution.
The majority of studies have been performed on low‐risk histological BCCs, located on low‐risk sites, the results of which are probably not applicable to high‐risk tumours. Only four studies have looked at high‐risk histological subtypes, and three studies looked at BCCs at high‐risk facial sites. More studies or subgroup analyses are required for morphoeic tumours.
Surgery remains the most effective treatment modality for BCC in terms of reducing recurrences, and there may be a slightly reduced recurrence rate with Mohs micrographic surgery (MMS) compared to surgical excision (SE); however, the 95% CI also includes the possibility of both increased risk and no difference between treatments (low‐certainty evidence). With regard to improvement of participant‐ and observer‐rated cosmetic outcomes, there may be little to no difference between MMS and SE (low‐certainty evidence); however, no raw data were available for this outcome. Radiotherapy is effective but probably worse than surgery (under frozen section margin control) in terms of the number of good cosmetic outcomes (moderate‐certainty evidence) and is therefore best reserved for tumours not amenable to surgery. Radiotherapy may also lead to increased recurrence compared to SE (low‐certainty evidence).
Non‐surgical treatments are less effective, but the evidence suggests that recurrence rates are acceptable and they are important options to offer patients. Imiquimod probably results in more recurrences than SE (moderate‐certainty evidence) and there is probably little to no difference between groups in the number of participant‐rated good/excellent cosmetic outcomes (low‐certainty evidence). However, imiquimod may increase the number of observer‐rated good/excellent cosmetic outcomes compared to SE (low‐certainty evidence). Overall, imiquimod has the best evidence to support its efficacy out of the non‐surgical treatments.
Moderate‐certainty evidence indicates that imiquimod probably leads to fewer recurrences than MAL‐PDT and there is probably little to no difference between these treatments in terms of observer‐rated good/excellent cosmetic outcomes (participant‐rated cosmetic outcomes were not measured in this comparison). MAL‐PDT may result in more recurrences at three years than SE (low‐certainty evidence; no useable data for measurement at five years), but probably increases the number of good/excellent cosmetic results (moderate‐certainty evidence).
Adverse effects with surgical interventions include wound infections, graft necrosis and post‐operative bleeding. Local adverse effects such as itching, weeping, pain and redness occur frequently with non‐surgical interventions. Treatment‐related adverse effects resulting in study modification or withdrawal occurred with imiquimod and MAL‐PDT.
The six studies in Studies awaiting classification may alter the conclusions of the review once assessed.
Implications for research
Currently, there is only low‐certainty evidence informing us on the efficacy of MMS against SE, with only one study assessing MMS against SE that met our inclusion criteria. Given this is the main comparison of our review, further studies assessing these treatments against each other are needed. Future studies exclusively assessing interventions for high‐risk BCC (high‐risk histological subtypes and high‐risk locations) are needed. As a minimum, future studies should present data on high‐risk tumours in subgroup analyses.
Cost:benefit ratios have an important impact on clinical practice and guidelines and so future systematic reviews on interventions for BCC should also include cost‐analyses as an outcome measure. This will allow us to answer important questions such as whether the higher operative costs and procedure times of MMS offset the potential higher number of recurrences seen with SE over time. It will also be important for imiquimod and 5‐FU cream as there is a big cost difference between these treatments, which may offset the differences in efficacy so defining this further will be important in future research to impact clinical practice.
Given that the radiotherapy studies included were all conducted over 20 years ago, and based on the fact that radiotherapy techniques and protocols have changed a lot since then, up‐to‐date studies assessing the efficacy of radiotherapy using current methods are needed, as these older studies may not be reflective of modern radiotherapy outcomes.
One of the key problems with RCTs on interventions for BCC is the lack of an agreed set of core outcome measures and also the lack of longer‐term outcomes for many of the studies which are now standard for most other cancer studies (for example, clinical recurrence at five years). An international group, in collaboration with the Core Outcome Measures in Effectiveness Trials (COMET) initiative and Cochrane Skin Group‐ Core Outcome Set Initiative (CSG‐COUSIN) have begun the task of developing broad consensus for a core outcome set for BCC intervention trials, which will be essential to improve the evidence we have for BCC in the future (Schlessinger 2017). For example, core outcome sets would determine whose opinion should be sought for assessing cosmetic outcomes (dermatologist, participant, or both), and when or how best to report it. BCC research should benefit greatly from this initiative, but future studies must also ensure that all outcomes are pre‐specified and registered prospectively to mitigate against the risk of selective outcome reporting bias.
Only a fifth of included RCTs followed participants up for at least three years and given that the majority of BCCs are likely to recur during the first three years after treatment, future studies should have follow‐up periods of at least three years. Further research is needed into what the optimal length of follow‐up should be as there is conflicting evidence documenting recurrences beyond five years. If at least 20% of recurrences occur beyond five years, then studies should follow up participants for up to 10 years. This will also impact the time points used for our primary outcome measures in future reviews.
Moreover, inadequate reporting of study methodology leads to biased estimates of treatment effects (Schulz 1995). Future studies on interventions for BCC must be well‐designed RCTs and should include a power calculation to ensure that sufficient numbers of participants are recruited to avoid problems with imprecision. Studies must also be rigorously reported and conform to the Consolidated Standards of Reporting Trials (CONSORT) statement (Schulz 2010). This will ensure a fair interpretation of the results and allow accurate appraisal and judgements to be made about the risk of bias and the overall certainty of evidence.
Given that curettage and cautery is commonly used in the treatment of low‐risk BCC, more evidence is needed to assess its efficacy as currently we only have one small study with only two years follow‐up that compared curettage and cautery with SE. Further RCTs with long‐term follow‐up are needed to assess its efficacy against other interventions including non‐surgical interventions. Further RCTs with long‐term follow‐up are needed for solasodine glycosides, ingenol mebutate, topical valproic acid, tazarotene, diclofenac, calcitriol and sinecatechin. These non‐surgical interventions should be compared against other non‐surgical interventions with established efficacy in treating BCC, such as imiquimod.