Interventions for Basal Cell Carcinoma

Abridged Cochrane Systematic Review and Grade Assessments

J. Thomson; S. Hogan; J. Leonardi-Bee; H. C. Williams; F. J. Bath-Hextall

The British Journal of Dermatology. 2021;185(3):499-511.

Abstract and Introduction

Abstract

Background: Basal cell carcinoma (BCC) is the most common cancer affecting white-skinned individuals, and the worldwide incidence is increasing. Although rarely fatal, BCC is associated with significant morbidity and costs.

Objectives: To assess the effects of interventions for primary BCC in immunocompetent adults.

Methods: We updated our searches of the following databases to November 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and LILACS. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation method. We used standard methodological procedures expected by Cochrane.

Results: We included 52 randomized controlled trials with 6990 participants (median age 65 years; range 20–95). Mean study duration was 13 months (range 6 weeks–10 years). Ninety-two per cent (n = 48/52) of studies exclusively included histologically low-risk BCC (nodular and superficial subtypes). The certainty of evidence was predominantly low or moderate for the outcomes of interest. Overall, surgical interventions have the lowest recurrence rates, and there may be slightly fewer recurrences with Mohs micrographic surgery over surgical excision for primary, facial BCC (high-risk histological subtype or located in the 'H-zone' or both) (low-certainty evidence). Nonsurgical treatments, when used for low-risk BCC, are less effective than surgical treatments, but recurrence rates are acceptable and cosmetic outcomes are probably superior.

Conclusions: Surgical interventions have lower recurrence rates and remain the gold standard for high-risk BCC. Of the nonsurgical treatments, topical imiquimod has the best evidence to support its efficacy for low-risk BCC. Priorities for future research include agreement on core outcome measures and studies with longer follow-up.

Introduction

Basal cell carcinoma (BCC) is the most common skin cancer and the most common cancer found in white-skinned individuals.^[1–3] BCCs are slow-growing, locally invasive, malignant (but not life-threatening), epidermal skin tumours.^[4,5] BCCs affect the head and neck region around 70% of the time, and the trunk and extremities around 30% of the time.^[6] A systematic review identified that the incidence of BCC is increasing in Europe by 5·5% annually.^[3] Between 2013 and 2015 there was a mean annual percentage increase of 5% in BCC incidence across the UK.^[6]

Clinicopathological features are used to differentiate BCCs into high- and low-risk subtypes, which has implications on management. High-risk BCCs include morphoeic, infiltrative and micronodular histological subtypes; the presence of perineural or perivascular invasion; size > 5 cm; a recurrent lesion; a centrofacial location, including periocular areas and the ears; and host immunosuppression.^[2] Low-risk BCCs include superficial and nodular histological subtypes when they are located at a low-risk site (e.g. not centrofacial location).

Numerous interventions are available for treating BCC, with the primary aim of treatment being to remove or destroy the lesion completely, resulting in cure with minimal risk of recurrence. Tumour removal should also be balanced against the patient's requirement for a good/acceptable cosmetic result. The first-line treatment of BCC is often surgical excision (SE) with Mohs micrographic surgery (MMS) reserved for high-risk sites. Numerous alternatives are available and include surgery under frozen section margin control; radiotherapy; photodynamic therapy (PDT); curettage and cautery ('electrodesiccation'); cryosurgery ('cryotherapy'); laser; electrochemotherapy; immunomodulators; topical chemotherapy; intralesional chemotherapy; systemic chemotherapy; and targeted molecular therapy (hedgehog pathway inhibitors).

This article is a summary of a Cochrane review that evaluated the effects of interventions for BCC,^[7] providing the best available evidence to healthcare providers and patients so that they can weigh up the risks and benefits of treatments, and to allow and promote shared decision-making.

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Table 1. Mohs micrographic surgery (MMS) vs. surgical excision (SE) for high-risk basal cell carcinoma ^a
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with SE	Risk with MMS	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Recurrence at 3 years	Study population		RR 0·64 (0·16–2·64)	331 (1 RCT)	⊕⊕⊝⊝ LOW^b	Study measured outcome at 30 months
Recurrence at 3 years	29/1000	19/1000 (5–77)	RR 0·64 (0·16–2·64)	331 (1 RCT)	⊕⊕⊝⊝ LOW^b	Study measured outcome at 30 months
Recurrence at 5 years	Study population		RR 0·61 (0·18–2·04)	259 (1 RCT)	⊕⊕⊝⊝ LOW^b	–
Recurrence at 5 years	52/1000	32/1000 (9–107)	RR 0·61 (0·18–2·04)	259 (1 RCT)	⊕⊕⊝⊝ LOW^b	–
Cosmetic outcome	Although a reported outcome, raw data were not available. The authors of the study state that, overall, cosmetic outcomes did not significantly differ between groups.^18,36 The cosmetic outcomes were judged by participants 18 months postoperatively, and photographs of a selected group of tumours (first 139 primary) were judged retrospectively by a panel of six individuals		NE	(1 RCT)	⊕⊕⊝⊝ LOW^c	–
Pain	No study addressed this outcome		NE	–	–	–
Early treatment failure	No study addressed this outcome		NE	–	–	–

Table 2. Imiquimod vs. surgical excision (SE) for low-risk basal cell carcinoma (BCC) ^a
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No. of participant (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with SE	Risk with imiquimod	Relative effect (95% CI)	No. of participant (studies)	Certainty of the evidence (GRADE)	Comments
Recurrence at 3 years	Study population		RR 10·30 (3·22–32·94)	401 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 3 years	16/1000	164/1000 (51–526)	RR 10·30 (3·22–32·94)	401 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 5 years	Study population		RR 7·73 (2·81–21·30)	383 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 5 years	23/1000	175/1000 (64–481)	RR 7·73 (2·81–21·30)	383 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Cosmetic outcome (good/excellent)	Study population		RR 1·00 (0·94–1·06)	326 (1 RCT)	⊕⊕⊝⊝ LOW^c	Participant-rated at 3 years on 6-point scale^d
Cosmetic outcome (good/excellent)	922/1000	922/1000 (866–977)	RR 1·00 (0·94–1·06)	326 (1 RCT)	⊕⊕⊝⊝ LOW^c	Participant-rated at 3 years on 6-point scale^d
Cosmetic outcome (good/excellent)	Study population		RR 1·70 (1·35–2·15)	344 (1 RCT)	⊕⊕⊝⊝ LOW^c	Observer-rated at 3 years on 6-point scale^d
Cosmetic outcome (good/excellent)	356/1000	606/1000 (481–766)	RR 1·70 (1·35–2·15)	344 (1 RCT)	⊕⊕⊝⊝ LOW^c	Observer-rated at 3 years on 6-point scale^d
Pain (moderate/severe)	Study population		RR 1·36 (0·98–1·88)	443 (1 RCT)	⊕⊕⊝⊝ LOW^e	Pain measured during treatment^f
Pain (moderate/severe)	219/1000	298/1000 (215–412)	RR 1·36 (0·98–1·88)	443 (1 RCT)	⊕⊕⊝⊝ LOW^e	Pain measured during treatment^f
Pain (moderate/severe)	Study population		RR 0·47 (0·29–0·77)	439 (1 RCT)	⊕⊕⊝⊝ LOW^e	Pain measured during follow-up^f
Pain (moderate/severe)	199/1000	94/1000 (58–153)	RR 0·47 (0·29–0·77)	439 (1 RCT)	⊕⊕⊝⊝ LOW^e	Pain measured during follow-up^f
Early treatment failure	No study addressed this outcome		NE	–	–	–

CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; NE, not estimable; RR, risk ratio; RCT, randomized controlled trial. ^aPatient or population: adults with low-risk BCC; setting: secondary care with outpatients from hospitals in the UK; intervention: 5% imiquimod cream; comparison: SE. ^bDowngraded one level for serious imprecision as only a single study with a small sample size and a wide 95% CI. ^cDowngraded one level for serious imprecision as only a single study with a small sample size and one level for serious risk of bias as unable to blind truly owing to the nature of interventions (i.e. presence or absence of scar will unblind to treatment allocation). ^dSix-point scale: unable to see lesion; very poor; poor; fair; good; excellent. ^eDowngraded one level for serious imprecision as only a single study with a small sample size and one level for serious risk of attrition bias as fewer pain data were available for the SE group. ^fMeasured on following scale: no pain; mild pain; mild-to-moderate pain; moderate pain; moderate-to-severe pain; and severe pain.

Table 3. Radiotherapy vs. surgical excision (SE) for high- and low-risk basal cell carcinoma (BCC) ^a
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No. of participant (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with SE	Risk with radiotherapy	Relative effect (95% CI)	No. of participant (studies)	Certainty of the evidence (GRADE)	Comments
Recurrence at 3 years	Study population		RR 19·11 (1·12–325·78)	347 (1 RCT)	⊕⊕⊝⊝ LOW^b	–
Recurrence at 3 years	0/1000	52/1000 (6–1883)	RR 19·11 (1·12–325·78)	347 (1 RCT)	⊕⊕⊝⊝ LOW^b	–
Recurrence at 4 years	Study population		RR 11·06 (1·44–84·77)	347 (1 RCT)	⊕⊕⊝⊝ LOW^c	–
Recurrence at 4 years	6/1000	64/1000 (8–487)	RR 11·06 (1·44–84·77)	347 (1 RCT)	⊕⊕⊝⊝ LOW^c	–
Cosmetic outcome (good/excellent)	Study population		RR 0·76 (0·63–0·91)	347 (1 RCT)	⊕⊕⊕⊝ MODERATE^d	Participant-rated at 4 years on 3-point scale.^e ITT analysis performed
Cosmetic outcome (good/excellent)	661/1000	502/1000 (416–601)	RR 0·76 (0·63–0·91)	347 (1 RCT)	⊕⊕⊕⊝ MODERATE^d
Cosmetic outcome	Study population		RR 0·48 (0·37–0·62)	347 (1 RCT)	⊕⊕⊕⊝ MODERATE^d	Observer-rated ("slightly visible") at 4 years on 3-point scale.^e ^fITT analysis performed
Cosmetic outcome	603/1000	290/1000 (223–374)	RR 0·48 (0·37–0·62)	347 (1 RCT)	⊕⊕⊕⊝ MODERATE^d
Pain	No study addressed this outcome		NE	–	–	–
Early treatment failure	No study addressed this outcome		NE	–	–	–

CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; ITT, intention to treat; NE, not estimable; RCT, randomized controlled trial; RR, risk ratio. ^aPatient or population: adults with high- and low-risk BCC; setting: secondary care with outpatients from a single hospital in France; intervention: radiotherapy; comparison: SE (with or without frozen section margin control). ^bDowngraded two levels for very serious imprecision due to very wide 95% CI (although excludes 1, there is a > 100-fold difference). ^cDowngraded one level for serious indirectness (outcome outside our prespecified timepoints) and downgraded one level for serious imprecision as only a single study with a small sample size. ^dDowngraded one level for serious risk of bias as unable to blind truly owing to the nature of interventions. ^eThree-point scale: bad; fair; good. ^fThree-point scale of scar appearance: bad, clearly marked, slightly visible.

Table 4. Methyl aminolaevulinate photodynamic therapy (MAL-PDT) vs. surgical excision (SE) for low-risk basal cell carcinoma (BCC) ^a
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with SE	Risk with MAL-PDT	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Recurrence at 3 years	Study population		RR 26·47 (1·63–429·92)	68 (1 RCT)	⊕⊕⊝⊝ LOW^b	–
Recurrence at 3 years	0/1000	364/1000 (49–13027)	RR 26·47 (1·63–429·92)	68 (1 RCT)	⊕⊕⊝⊝ LOW^b	–
Cosmetic outcome (good/excellent)	Study population		RR 1·18 (1·09–1·27)	309 (2 RCTs)	⊕⊕⊕⊝ MODERATE^c	Participant-rated at 1 year on 4-point scale^d
Cosmetic outcome (good/excellent)	825/1000	973/1000 (899–1000)	RR 1·18 (1·09–1·27)	309 (2 RCTs)	⊕⊕⊕⊝ MODERATE^c	Participant-rated at 1 year on 4-point scale^d
Cosmetic outcome (good/excellent)	Study population		RR 1·87 (1·54–2·26)	256 (2 RCTs)	⊕⊕⊕⊝ MODERATE^c	Observer-rated at 1 year on a 4-point scale^d
Cosmetic outcome (good/excellent)	466/1000	871/1000 (717–1000)	RR 1·87 (1·54–2·26)	256 (2 RCTs)	⊕⊕⊕⊝ MODERATE^c	Observer-rated at 1 year on a 4-point scale^d
Pain	Study population		RR 2·20 (0·60–8·03)	101 (1 RCT)	⊕⊕⊝⊝ LOW^e	Study reported frequency of 'pain in skin' and 'burning sensation of skin' as part of AEs
Pain	61/1000	135/1000 (37–492)	RR 2·20 (0·60–8·03)	101 (1 RCT)	⊕⊕⊝⊝ LOW^e
Early treatment failure	Study population		RR 6·66 (1·22–36·41)	173 (2 RCTs)	⊕⊕⊕⊝ MODERATE^f
Early treatment failure	11/1000	77/1000 (14–419)	RR 6·66 (1·22–36·41)	173 (2 RCTs)	⊕⊕⊕⊝ MODERATE^f

AE, adverse event; CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; RCT, randomized controlled trial; RR, risk ratio. ^aPatient or population: adults with low-risk BCC; setting: secondary care with outpatients from hospitals in Brazil, the UK, Germany, Switzerland and Australia; intervention: MAL-PDT; comparison: SE. ^bDowngraded two levels for very serious imprecision owing to very wide 95% CI (although excludes 1, there is a > 100-fold difference). ^cDowngraded one level for serious risk of bias as unable to blind truly owing to the nature of interventions. ^dFour-point scale: poor (extensive occurrence of scarring, atrophy or induration); fair (slight-to-moderate occurrence of scarring, atrophy or induration); good (no scarring, atrophy or induration, and moderate redness or increase in pigmentation vs. adjacent skin); excellent (no scarring, atrophy or induration, and slight or no redness or change in pigmentation vs. adjacent skin). ^eDowngraded two levels for very serious imprecision as very wide 95% CI, indicating the possibility of important benefit or harm. ^fDowngraded one level for serious imprecision due to small sample size and wide 95% CI.

Table 5. Aminolaevulinic acid photodynamic therapy (ALA-PDT) vs. surgical excision (SE) for low-risk basal cell carcinoma (BCC) ^a
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with SE	Risk with ALA-PDT	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Recurrence at 3 years	Study population		RR 10·87 (2·63–44·95)	173 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 3 years	23/1000	247/1000 (60–1000)	RR 10·87 (2·63–44·95)	173 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 5 years	Study population		RR 11·91 (2·90–48·95)	173 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 5 years	23/1000	271/1000 (66–1000)	RR 11·91 (2·90–48·95)	173 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Cosmetic outcome	No study addressed this outcome		NE	–	–	–
Pain	No study addressed this outcome		NE	–	–	–
Early treatment failure	Study population		RR 3·18 (0·66–15·32)	171 (1 RCT)	⊕⊕⊝⊝ LOW^c	–
Early treatment failure	23/1000	72/1000 (15–348)	RR 3·18 (0·66–15·32)	171 (1 RCT)	⊕⊕⊝⊝ LOW^c	–

CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; NE, not estimable; RCT, randomized controlled trial; RR, risk ratio. ^aPatient or population: adults with low-risk BCC; setting: secondary care with outpatients from a single-centre in the Netherlands; intervention: ALA-PDT; comparison: SE. ^bDowngraded one level for serious imprecision as only a single study with a small sample size and a wide 95% CI. ^cDowngraded two levels for very serious imprecision as very wide 95% CI, indicating the possibility of important benefit or harm.

Table 6. Imiquimod cream vs. methyl aminolaevulinate photodynamic therapy (MAL-PDT) for low-risk basal cell carcinoma (BCC) ^a
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No. of participant (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with PDT	Risk with imiquimod cream	Relative effect (95% CI)	No. of participant (studies)	Certainty of the evidence (GRADE)	Comments
Recurrence at 3 years	Study population		RR 0·44 (0·32–0·62)	277 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 3 years	516/1000	227/1000 (165–320)	RR 0·44 (0·32–0·62)	277 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 5 years	Study population		RR 0·42 (0·31–0·57)	228 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 5 years	686/1000	288/1000 (213–391)	RR 0·42 (0·31–0·57)	228 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Cosmetic outcome (excellent/good)	Study population		RR 0·98 (0·84–1·16)	370 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	Blinded observer-rated at 1 year on 4-point scale^c
Cosmetic outcome (excellent/good)	624/1000	611/1000 (524–723)	RR 0·98 (0·84–1·16)	370 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	Blinded observer-rated at 1 year on 4-point scale^c
Pain (moderate/severe)	Study population		RR 0·60 (0·41–0·87)	371 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	During treatment: week of treatment with highest frequency of reported moderate/severe pain (week 6 for imiquimod, treatment cycle 2 for PDT)
Pain (moderate/severe)	305/1000	183/1000 (125–266)	RR 0·60 (0·41–0·87)	371 (1 RCT)	⊕⊕⊕⊝ MODERATE^b
Early treatment failure	Study population		RR 0·64 (0·37–1·09)	385 (1 RCT)	⊕⊕⊕⊝ MODERATE^d	–
Early treatment failure	158/1000	101/1000 (59–172)	RR 0·64 (0·37–1·09)	385 (1 RCT)	⊕⊕⊕⊝ MODERATE^d	–

CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; RCT, randomized controlled trial; RR, risk ratio. ^aPatient or population: adults with low-risk BCC; setting: secondary care with outpatients from seven hospitals in the Netherlands; intervention: 5% imiquimod cream; comparison: MAL-PDT. ^bDowngraded one level for serious imprecision as only a single study with a small sample size. ^cFour-point scale (poor, fair, good, excellent). ^dDowngraded one level for serious imprecision as only a single study with a small sample size and a wide 95% CI.

Table 7. Imiquimod cream vs. fluorouracil (5-FU) cream for low-risk basal cell carcinoma (BCC) ^a
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with 5-FU cream	Risk with imiquimod cream	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Recurrence at 3 years	Study population		RR 0·68 (0·47–0·99)	291 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 3 years	342/1000	233/1000 (161–339)	RR 0·68 (0·47–0·99)	291 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 5 years	Study population		RR 0·62 (0·44–0·87)	250 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Recurrence at 5 years	460/1000	285/1000 (202–400)	RR 0·62 (0·44–0·87)	250 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	–
Cosmetic outcome (excellent/good)	Study population		RR 1·07 (0·90–1·26)	377 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	Observer-rated at 1 year on 4-point scale^c
Cosmetic outcome (excellent/good)	575/1000	615/1000 (518–725)	RR 1·07 (0·90–1·26)	377 (1 RCT)	⊕⊕⊕⊝ MODERATE^b	Observer-rated at 1 year on 4-point scale^c
Pain (moderate/severe)	Study population		RR 1·46 (0·89–2·38)	365 (1 RCT)	⊕⊕⊕⊝ MODERATE^d	During treatment: comparing the week of treatment with highest frequency of reported moderate/severe pain (week 6 for imiquimod, week 4 for 5-FU cream)
Pain (moderate/severe)	125/1000	183/1000 (111–298)	RR 1·46 (0·89–2·38)	365 (1 RCT)	⊕⊕⊕⊝ MODERATE^d
Early treatment failure	Study population		RR 0·83 (0·47–1·46)	387 (1 RCT)	⊕⊕⊝⊝ LOW^e	–
Early treatment failure	121/1000	101/1000 (57–177)	RR 0·83 (0·47–1·46)	387 (1 RCT)	⊕⊕⊝⊝ LOW^e	–

CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; RCT, randomized controlled trial; RR, risk ratio. ^aPatient or population: adults with low-risk BCC; setting: secondary care with outpatients from seven hospitals in the Netherlands; intervention: imiquimod cream; comparison: 5-FU cream. ^bDowngraded one level for serious imprecision as only a single study with a small sample size. ^cFour-point scale: poor; fair; good; excellent. ^dDowngraded one level for serious imprecision as only a single study with a small sample size and a wide 95% CI. ^eDowngraded two levels for very serious imprecision as very wide 95% CI, indicating the possibility of important benefit or harm.