Abbreviations
- AE
adverse event
- BCC
basal cell carcinoma
- BD
Bowen’s disease
- CI
confidence interval
- CLC
complete lesion clearance
- CLR
complete lesion response
- CrI
credible interval
- CRP
cumulative recurrence probability
- CTx
cryotherapy
- FU
fluorouracil
- HR
hazard ratio
- ICER
incremental cost effectiveness ratio
- ITT
intention-to-treat
- IM
ingenol mabutate
- IMQ
imiquimod
- MAL
methylaminolevulinate
- MAL-PDT
methylaminolevulinate photodynamic therapy
- NA
not applicable
- NMA
network meta-analysis
- MMS
Mohs micrographic surgery
- NMSC
non-melanoma skin cancer
- NR
not reported
- nBCC
nodular basal cell carcinoma
- OR
odds ratio
- PDT
photodynamic therapy
- RR
relative risk
- RTx
radiotherapy
- sBCC
superficial basal cell carcinoma
- SCC
squamous cell carcinoma
- SUCRA
surface under the cumulative ranking curve
- Tx
treatment
- vs
versus
Context and Policy Issues
Non-melanoma skin cancers (NMSC) include mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).1 BCC is a superficial, slow growing papule or nodule that arises from keratinocytes near the basal layer of the epidermis (outer layer of skin).2,3 Metastasis is rare, however the local growth may be very destructive.2,4 BCC has several subtypes; the most common subtype is the nodular type (incidence 45% to 60%), followed by the superficial types (15% to 35%).5 The more aggressive types of BCC are less frequent and these include infiltrative (10% to 29%), morpheaform (about 9%), micronodular (about15%), and adenoid forms (unknown incidence).5 SCC is a malignant tumor of the epidermal keratinocytes and may cause considerable local destruction and in advanced stages can metastasize.6,7 Bowen’s disease (BD) is in situ SCC and the risk of progression to invasive SCC is generally estimated to be about 3%.8
Incidence rates of NMSC are variable across countries and approximately 80% of NMSC are BCC.9 BCC is the most common type of skin cancer and its incidence is increasing worldwide.1,2,5,10 It is estimated that the annual increase in incidence ranges between 3% to 10%.1 According to one estimate, greater than four million new cases of BCC occur annually in the US. BCC is generally most common in fair-skinned individuals with a history of sun exposure.2 SCC is the second most common type of skin cancer and according to one estimate greater than one million cases occur annually in the US, with 2500 deaths.6 The incidence of BD is 28 per 100,000 in women and 22 per 100,000 in men in Canada and 15 per 100,000 people in Minneapolis (USA).8 The cost associated with treating NMSC is estimated to be greater than $US 400 million in the US Medicaid population.5
A variety of treatment options are available for BCC and SCC, such as surgical excision; radiotherapy (RTx,; cryotherapy (CTx), photodynamic therapy (PDT), and topical agents such as imiquimod (IMQ) and fluorouracil (FU).1,2,4–6 Radiotherapy uses high energy X-rays to destroy the cancer cells, CTx uses liquid nitrogen to destroy tissue by freezing it to – 196°C, and in PDT visible light (blue or red) and a light-sensitive compound is used to generate free radicals, which induce cell damage and death.8,11 FU reduces cell proliferation and induces cell death, particularly in cells with high cell division rates.11,12 IMQ is an immune-response modifier and leads to strong anti-viral and antitumor activity.8,11 Treatment with surgery is generally considered as the gold standard. However, surgical interventions have potential disadvantages such as bleeding, scarring, and risk of infection.13 Also, patients may refuse surgery or may not be able to tolerate surgical procedures. As a result non-surgical treatments are gaining favor. However, there appears to be no consensus as to which treatments are optimal.
The purpose of this review is to compare the clinical effectiveness and cost-effectiveness of IMQ to other treatment modalities for the treatment of BCC or SCC. This report is the first in the series of three reports on IMQ. The following two reports will be on actinic keratosis and genital warts.
Research Questions
What is the clinical effectiveness of imiquimod for the treatment of basal cell or squamous cell carcinoma?
What is the cost-effectiveness of imiquimod for the treatment of basal cell or squamous cell carcinoma?
Key Findings
A network meta-analysis including patients with basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Bowen’s disease (in situ SCC) and comparing treatments with imiquimod (IMQ), photodynamic therapy (PDT), surgical excision, cryotherapy (CTx), radiotherapy (RTx), fluorouracil (FU), and placebo showed that for complete lesion clearance, surgical excision was the most favorable followed in order by IMQ, CTx, PDT, FU and placebo; for cumulative recurrence probability, surgical excision was the most favorable followed in order by RTx, FU, IMQ, CTx, PDT; and for adverse events, placebo and CTX were the most favorable (least probability of occurrence of adverse events), followed in order by surgical excision, FU and IMQ.
One randomized controlled trial (RCT) showed that for patients with BCC the success rate (i.e., no initial treatment failure or recurrence) up to 5 years of follow-up was higher with surgical intervention compared with IMQ treatment. One RCT showed that that for patients with superficial BCC, greater tumor free survival was achieved with IMQ compared with PDT, up to three years of follow-up.
From one study conducted in the Netherlands and based on one year follow-up results, IMQ and FU were more cost-effective than MAL-PDT for treatment of superficial BCC.
Findings need to be interpreted in the light of limitations (mainly variability across the studies with respect to population, follow-up times and lesion type).
Methods
Literature Search Methods
A limited literature search was conducted on key resources including MEDLINE, Embase, PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology assessment agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and economic studies. Conference abstracts were excluded from the search results. The search was also limited to English language documents published between January 1, 2012 and August 4, 2017.
Rapid Response reports are organized so that the evidence for each research question is presented separately.
Selection Criteria and Methods
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in .
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in , they were duplicate publications, or were published prior to 2012. Systematic reviews with all studies included in at least one of the selected systematic reviews were excluded.
Critical Appraisal of Individual Studies
The included systematic reviews were critically appraised using AMSTAR,14 randomized controlled trials (RCTs) were critically appraised using the Downs and Black checklist,15 and economic studies were assessed using the Drummond checklist.16 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively.
Summary of Evidence
Quantity of Research Available
A total of 204 citations were identified in the literature search. Following screening of titles and abstracts, 188 citations were excluded and 16 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, seven publications were excluded for various reasons, while nine publications1,5,8–10,12,17–19 met the inclusion criteria and were included in this report. Of these nine publications, three publications9,12,17 provided relevant information for one RCT and two publications10,17 provided relevant information for one RCT, hence there were six unique studies: three systematic reviews,1,5,8 two RCTs9,10,12,17,17 and one economic study.19
Appendix 1 describes the PRISMA flowchart of the study selection.
Summary of Study Characteristics
Study characteristics are summarized below and details are presented in Appendix 2, to .
Systematic reviews and clinical studies
Study Design
Three relevant systematic reviews1,5,8 were identified. The systematic reviews had broad objectives, hence only the included studies that were relevant for our report were considered. One systematic review8 included nine RCTs of which one RCT published in 2006 was relevant for our report. One systematic review5 included 29 RCTs and four non-randomized studies of which five RCTs published between 2005 and 2013 were relevant for our report. One systematic review1 which included a network meta-analysis included 15 RCTs and three prospective studies, published between 1986 and 2015.
Two relevant RCTs were identified. One RCT presented data in three reports9,12,18 and one RCT presented data in two reports.10,17 Both RCTs were multicenter non-inferiority trials.
Country of Origin
One systematic review8 was published in 2013 by the Cochrane Collaboration, one systematic review5 was published in 2014 from USA, and one systematic review1 was published in 2017 from China. One RCT10 was published in 2014 from the UK with additional information (long-term follow-up data)17 published in 2017. One RCT12 was published in 2013 from the Netherlands with additional information (subgroup analysis and long-term follow-up data)9,18 published in 2015 and 2016.
Patient Population
One systematic review8 included 31 adult patients with BD (in situ SCC) with 65% being females. One systematic review5 included patients with BCC; age and proportion of females were not reported. One systematic review1 included patients with BCC, SCC and BD; patient age ranged between 21 years and 99 years and proportion of females ranged from 28% to 84% in the included studies.
One RCT10 included 501 adult patients with nodular BCC (nBCC) or superficial BCC (sBCC), with median age ranging between 67 years and 69 years and proportion of females ranging between 40% and 41% in the two treatment groups. One RCT12 included 601 adult patients with sBCC, with median age ranging between 62 years to 64 years, and proportion of females ranging between 47% and 53% in the three treatment groups.
Interventions and Comparators
One systematic review8 compared IMQ with placebo; one systematic review5 compared IMQ with methylaminolevulinate photodynamic therapy (MAL-PDT), FU, RTx and vehicle; and one systematic review1 compared IMQ, PDT, surgical excision, CTx, RTx, FU, and vehicle with each other in a NMA. The terms vehicle and placebo appear to be used interchangeably in the literature.
One RCT10 compared IMQ with surgical excision and one RCT12 compared MAL-PDT, IMQ and FU.
Outcomes
All three systematic reviews1,5,8 reported on lesion clearance rate, recurrence rate and adverse events. Both RCTs9,10,12,17,18 reported on success rate, cosmetic appearance and adverse events. Results of subgroup analyses with respect to age, gender, tumor location, and tumor size were available in two of the publications9,18 for one RCT.9,12,18
Economic study
One relevant cost-effectiveness study19 was identified. It was published in 2014 from the Netherlands. It included patients with superficial BCC (sBCC) and compared MAL-PDT with IMQ and FU, using a health care perspective and time horizon of one year, and reported on the incremental cost-effectiveness ratio (ICER) defined as the incremental cost per additional patient free from tumor recurrence. A health-care perspective was used as other costs such as travel costs or use of services outside the healthcare were expected to be minimal. Also, productivity loss due to the condition was considered to be minimal as majority of the patients had reached retirement age. The clinical data was obtained from an RCT conducted by the same group conducting the economic analysis. Bootstrap simulations (1000) were conducted to quantify uncertainty surrounding ICER.
Summary of Critical Appraisal
The critical appraisal of the included systematic reviews, RCTs, and economic study are presented below and details are available in Appendix 3, to .
Systematic review
In all three systematic reviews1,5,8 the objective, and inclusion and exclusion criteria were stated; multiple databases were searched; study selection was described; list of included studies was provided; and study characteristics were presented. Two systematic reviews5,8 also searched trial registries and the reference list of relevant articles. A list of excluded studies was presented in one systematic review8 and not presented in two systematic reviews.1,5 Article selection was done in duplicate in two systematic reviews,5,8 and was unclear in one systematic review.1 Data extraction was done in duplicate in two systematic review1,8 and was unclear in one systematic review.5 Quality assessment of studies was conducted in two systematic reviews5,8 and was not conducted in one systematic review.1 Quality was judged by the authors to be limited in one systematic review8 and ranged between moderate and high in one systematic review.5 In one systematic review8 meta-analysis was conducted when feasible; in one systematic review5 individual studies were described narratively and meta-analysis was not conducted; and in one systematic review1 a network meta-analysis was presented. In one systematic review8 investigation of publication bias using Funnel plots was planned but no results were presented, possibly due to too few studies available for constructing a meaningful Funnel plot. In one systematic review1 publication bias was explored and there were no apparent issues, and in one systematic review5 it was unclear if publication bias was explored. In two systematic reviews1,8 the authors stated that there were no conflicts of interest. In one systematic review5 one author had association with industry and the remaining two authors had no conflicts of interest.
RCT
In both RCTs9,10,12,17,18 the objectives and inclusion and exclusion criteria were stated, patient characteristics, interventions and outcomes were described, sample size was calculated and met; computer generated block randomization was done; modified intention-to-treat (ITT) analysis was conducted; and the authors mentioned that there were no conflicts of interest. Patients lost to follow up or not considered in the analysis were unequal in the treatment groups ranged between 14% and 37%; this may impact findings but the direction of impact is unclear. One RCT9,12,18 included subgroup analyses, however the subgroups had not been planned a priori, hence the possibility of bias cannot be ruled out.
Economic study
In the economic study19 the objectives, treatments compared, time horizon, perspective, clinical data source and cost data source were stated and appeared to be appropriate. There was no discounting as the time horizon was one year. Incremental cost-effectiveness ratio (ICER) was calculated and sensitivity analyses were conducted. Conclusions were consistent with the results. Indirect costs were not considered, however, indirect costs such as those resulting from travel costs and productivity loss were expected to be minimal as explained above in the Study Characteristics section.
Summary of Findings
Findings are summarized below and details are available in Appendix 4, .
What is the clinical effectiveness of imiquimod for the treatment of basal cell or squamous cell carcinoma?
Lesion clearance
Three RCTs from two systematic reviews5,8 showed that for patients with BCC or BD, treatment with IMQ resulted in statistically significantly greater lesion clearance compared to control (vehicle or placebo). One relevant RCT included in one systematic review5 showed that for patients with BCC, lesion clearance was similar in both the IMQ group and RTx group. One systematic review1 on patients with BCC, SCC, and BD and including a network meta-analysis comparing seven treatment options (IMQ, PDT, surgical excision, CTx, RTx, FU, and vehicle) showed that for complete lesion clearance, as estimated from the surface under the cumulative ranking curve (SUCRA), surgical excision was the most favorable followed in order by IMQ, CTx, PDT, FU and vehicle.
Recurrence
One relevant RCT included in one systematic review8 showed that for patients with BD, there was recurrence in the placebo group but not in the IMQ group at 72 weeks follow-up. One relevant RCT included in one systematic review5 showed that for patients with BCC, undergoing Mohs micrographic surgery there was no recurrence in either the group pretreated with IMQ or the group pre-treated with vehicle, at 20 month follow-up. One relevant RCT included in one systematic review5 showed that for patients with BCC, recurrence was statistically significantly lower with IMQ compared to MAL-PDT, however there were no statistically significant between-group differences for IMQ compared with FU. One systematic review1 including a network meta-analysis on patients with BCC, SCC, and BD and comparing seven treatment options (IMQ, PDT, surgical excision, CTx, RTx, FU, and vehicle) in terms of the cumulative recurrence probability, showed that as estimated from SUCRA surgical excision was the most favorable and followed in order by RTx, FU, IMQ, CTx, PDT.
One RCT10,17 showed that for patients with BCC, the success rate (i.e., no initial treatment failure or recurrence) was higher in the surgical group compared with the IMQ group during one to five years of follow-up. Although IMQ was inferior to surgery, this RCT showed that for lesions that responded early to IMQ, the benefit was sustained. One RCT9,12,18 showed that for patients with superficial BCC, with respect to tumor free survival, IMQ was superior and FU was not inferior compared with MAL-PDT for patients with superficial BCC. This RCT included subgroup analyses and showed that for older patients with superficial BCC located on lower extremities MAL-PDT appeared to be more favorable than IMQ.
Adverse events
Two relevant RCTs (comparing IMQ to vehicle or placebo) from two systematic reviews5,8 showed that for patients with BCC or BD, the IMQ group experienced localized inflammatory reactions. One relevant RCT from one systematic review5 showed that for patients with BCC, the IMQ and FU groups experienced greater frequency of moderate to severe local reactions compared with MAL-PDT. One relevant RCT from one systematic review5 showed that for patients with BCC, the IMQ group experienced greater adverse effects (frequency and severity not reported) and less tolerability during treatment compared with RTx, and RTx was associated with dry eyes and loss of eyelashes post-treatment. One systematic review1 including a network meta-analysis on patients with BCC, SCC, and BD, and comparing seven treatment options (IMQ, PDT, surgical excision, CTx, RTx, FU, and vehicle) showed that with respect to adverse events, as estimated from SUCRA, vehicle and CTX were the most favorable (least probability of occurrence of adverse events), followed in order by surgical excision, FU and IMQ.
One RCT10 showed that for patients with BCC, adverse events were numerically slightly higher in the IMQ group compared to the surgical group. In one RCT9,12,18 the IMQ and FU groups more often experienced moderate to severe adverse effects compared to the MAL-PDT group.
What is the cost-effectiveness of imiquimod for the treatment of basal cell or squamous cell carcinoma?
For one-year of follow-up, the total mean costs for treating patients with superficial BCC were €680 with MAL-PDT, €526 with IMQ, and €388 with FU. The ICERs indicated that in comparison to MAL-PDT both IMQ and FU were dominant hence both IMQ and FU were more effective and less costly compared to MAL-PDT. Sensitivity analysis using a lower cost for MAL-PDT still maintained dominance for IMQ and FU. The ICER for IMQ compared to FU was €4451 per effectiveness. Effectiveness was measured as an additional patient free from tumor recurrence. Using a lower treatment cost for IMQ by using 30 sachets instead of the usual 36 sachets, the ICER for IMQ compared to FU was €3451 per effectiveness. As there are no threshold values for disease specific cost-effectiveness ratios using additional patient free of tumor recurrence as a measure of effectiveness, the authors calculated a threshold based on cost of management of recurrence. Recurrent superficial BCC can be easily treated by surgical excision which was estimated to cost €700. Considering this as the threshold, IMQ would not be cost-effective compared to FU. Threshold values in terms of quality adjusted life years (QALY) were not used as superficial BCC and its treatment were not considered to significantly impact general quality of life and mortality, as superficial BCC does not metastasize.
Limitations
Two systematic reviews1,5 had several overlapping studies hence results are not exclusive. However, the perspectives were different: one systematic review5 described the studies narratively and one systematic review1 included a network meta-analysis.
The results of the network meta-analyses need to be interpreted with caution as there was heterogeneity across the studies with respect to population, lesion size and location, and follow-up times. In addition, for several treatment comparisons data were available from a single study.
Follow-up times for some outcomes in some studies were not specified, hence how long the effect was sustained was unclear.
Findings from the subgroup analyses in one RCT9,12,18 need to be interpreted with caution as the subgroups were not decided a priori and have potential for bias.
The cost-effectiveness analysis had a one year time horizon hence the cost-effectiveness in the long term is unclear.
Findings need to be interpreted in the light of the limitations presented above.
It was unclear if any of the primary studies were conducted in Canada hence, generalizability to the Canadian setting is difficult.
Conclusions and Implications for Decision or Policy Making
Three systematic reviews,1,5,8 two RCTs,9,10,12,17,18 and one cost-effectiveness study19 that compared IMQ with other treatments for patients with BCC, SCC, and BD were identified.
In patients with BCC or BD, treatment with IMQ appeared to be better than placebo or vehicle with respect to lesion clearance and tumor recurrence but was associated with localized inflammatory reactions. A network meta-analysis including patients with BCC, SCC and BD, and comparing seven treatment options (IMQ, PDT, surgical excision, CTx, RTx, FU, and placebo) showed that for complete lesion clearance, surgical excision was the most favorable followed in order by IMQ, CTx, PDT, FU and placebo; for cumulative recurrence probability, surgical excision was the most favorable and followed in order by RTx, FU, IMQ, CTx, PDT; and for adverse events, placebo and CTX were the most favorable ( least probability of occurrence of adverse events), followed in order by surgical excision, FU and IMQ.
One randomized controlled trial (RCT) showed that for patients with BCC the success rate (i.e., no initial treatment failure or recurrence) up to 5 years of follow-up was higher with surgical intervention compared with IMQ treatment. One RCT showed that that for patients with superficial BCC, greater tumor free survival was achieved with IMQ compared with PDT, up to three years of follow-up.
Based on one year follow-up results, IMQ and FU were more effective and less costly than MAL-PDT for treatment of superficial BCC. Cost-effectiveness in the long term is unclear.
BCC lesions have different characteristics and the associated risks vary. Hence to administer the appropriate course of treatment, the type of lesion and clinical risk factors need to be considered.5
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Appendix 1. Selection of Included Studies
Appendix 2. Characteristics of Included Publications
Table 2Characteristics of Included Systematic Reviews
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| Author, Year, Country | Type and Number of Primary Studies Included, Aim | Population Characteristics | Comparisons | Outcome |
|---|
| Bath-Hextall,8 2013, Cochrane Collaboration | This systematic review included 9 RCTs of which one RCT published in 2006 from the UK was relevant for our report.
Patients recruited from a dermatology outpatient department
Aim: To assess the effects of various therapies for cutaneous BD | Adult patients with BD (in situ SCC)
N = 31 patients (31 lesions; 15 in IMQ, and 16 in placebo)
Age (years) : NR
% Female: 65%
The two treatment groups were similar at baseline, except the mean duration and size of lesion were greater in the IMQ group compared to the placebo group | IMQ versus placebo | Clearance rate, recurrence, adverse events
Follow-up: 72 weeks |
| Clark,5 2014, USA | This systematic review included 29 RCTs and 4 non-randomized studies of which 5 RCTs published between 2005 and 2013 were relevant for our report)
Aim: To assess the effects of various treatment options for BCC | Patients with BCC
N = 1588 (numbers in individual RCTs varied between 27 and 724).
Age (years): NR
% Female: NR | MAL-PDT versus IMQ versus FU (1 RCT);
IMQ versus RTx (1 RCT);
MMS plus pre-Tx with IMQ versus MMS plus pre-Tx with vehicle (1 RCT);
IMQ vs vehicle (2 RCTs) | Clearance rate, recurrence, adverse events.
Follow-up: NR |
| Lv,1 2017, China | This systematic review included 18 studies (15 RCTs and 3 prospective studies) published between 1986 and 2015
Aim: To assess the comparative clinical efficacy and safety of PDT, surgical excision, CTx, IMQ, RT, FU, and vehicle for treating NMSC (includes BCC. SCC, BD) by conducting a network meta-analysis. | Adults with NMSC (BCC, SCC, or BD).
N = 3706 (numbers in individual studies ranged from 35 to 601)
Age (range) (years): 21 to 99
% Female: 28% to 84% (for 16 studies) and was not reported for 2 studies | Comparison between PDT, surgical excision, CTx, IMQ, RT, FU, and vehicle | Complete lesion response (CLR), complete lesion clearance (CLC), cumulative recurrence probability (CRP), adverse events (AEs).
Follow-up ranged between 3 and 60 months |
BCC = basal cell carcinoma; BD = Bowen’s disease; CTx = cryotherapy; FU = flurouracil; IMQ = imiquimod; MAL = methylaminolevulinate; MAL-PDT = methylaminolevulinate photodynamic therapy ; MMS = Mohs micrographic surgery; NMSC = non-melanoma skion cancer; NR = not reported; PDT = photodynamic therapy; RCT = randomized controlled trial, RTx = radiotherapy; SCC = squamous cell carcinoma.
Table 3Characteristics of Included Clinical Studies
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| Author, Year, Country | Study Design | Population Characteristics | Comparison | Outcome, Follow-up |
|---|
| Bath-Hextall,10 2014, UK | RCT (multicenter , parallel group, pragmatic, non-inferiority trial)
Setting: 12 centers in the UK The non-inferiority margin was calculated to be a relative risk of 0.87
Aim: To assess the effectiveness of IMQ cream versus surgical excision (SuE) in patients with low-risk BCC | Adults with nodular BCC or superficial BCC
N = 501 (254 in IMQ, 247 in SuE ); patients in modified ITT analysis: 467 (247 in IMQ, 220 in SuE)
For modified ITT population: Age (median [IQR]) (years): 69 (61 to 76) in IMQ, 67 (59 to 74) in SuE.
% Female: 41% in IMQ, 40% in SuE
BCC type: 49% had nodular BCC, 51% had superficial BCC | IMQ (5%) versus SuE
IMQ was applied once daily for 6 weeks for superficial BCC and for 12 weeks for nodular BCC
Surgery: Simple excisional surgery with 4 mm margins. Dermatology consultants and dermatology trainees performed the surgery in line with usual local hospital arrangements, indicative of the pragmatic nature of the trial | Primary outcome: Clinical success after 3 years from start of treatment.
Secondary outcome: Clinical success after 1 and 2 years; time to first failure, cosmetic appearance, and pain.
Adverse events.
Clinical success defined no initial treatment failure or signs of subsequent local recurrence as reviewed by the consultant dermatologist.
Follow-up: up to 5 years |
| Roozeboom,18 2016, The Netherlands; Roozeboom,9 2015, The Netherlands; Arits,12 2013, The Netherlands | RCT (multicenter, single- blind, non-inferiority trial)
Setting: Maastricht University Medical Center and 6 other hospitals in the Netherlands.
Aim: To assess the comparative effectiveness of MAL-PDT, IMQ, and FU and the comparative effectiveness of MAL-PTD and IMQ with respect to various subgroups of patients with superficial BCC | Adults with superficial BCC
N = 601 (202 in MAL-PDT, 198 in IMQ, and 201 in FU)
Age (median [range]) (years): 63 (26 to 87) in MAL-PDT, 62 (30 to 91) in IMQ, and 64 (35 to 86) in FU.
% Female: 53% in MAL-PDT, 49% in IMQ, and 47% in FU | MAL-PDT versus IMQ (5%) versus FU.
MAL-PDT involves application of 16% MAL (Metvix) to the lesions, incubation for 3 hours, removal of excess cream and then irradiation with a light emitting diode. Two such treatment sessions, I week apart were done.
IMQ (5%) was applied to the tumor including 5 to 10 mm of the surrounding area. It was applied once daily for 5 days a week for 6 weeks.
FU (5%) was applied to the tumor including 5 to 10 mm of the surrounding area. It was applied twice daily for 4 weeks | Primary outcome: success rate (probability that a patient was free of tumor recurrence at both 3 months and 12 months of follow up.
Secondary outcome: aesthetic outcome, compliance, adverse events.
Follow-up: up to 3 years |
BCC = basal cell carcinoma; FU = fluorouracil; ICER = incremental cost-effectiveness ratio; IMQ = imiquimod; MAL-PDT = methylaminolevulinate photodynamic therapy ; RCT = randomized controlled trial, SuE = surgical excision.
Table 4Characteristics of Included Economic Studies
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| Author, Year, Country | Study Design | Perspective, Time Horizon, Currency, Discounting | Population | Interventions | Outcomes |
|---|
| Arits,19 2014, The Netherlands | Cost-effectiveness study
Aim: To assess the cost-effectiveness of IMQ and FU compared with MAL-PDT | Healthcare perspective, time horizon = 1 year , currency = €, discounting not necessary as 1 year time horizon | Patients with sBCC | MAL-PDT, IMQ, and FU | ICER
ICER defined as the incremental cost per additional patient free from tumor recurrence |
BCC = basal cell carcinoma; FU = fluorouracil; ICER = incremental cost-effectiveness ratio; IMQ = imiquimod; MAL-PDT = methylaminolevulinate photodynamic therapy ; sBCC = superficial basal cell carcinoma.
Appendix 3. Critical Appraisal of Included Publications
Table 5Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR
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| Strengths | Limitations |
|---|
| Bath-Hextall,8 2013, Cochrane Collaboration |
|---|
The objective was clearly stated. The inclusion criteria were stated. The exclusion criteria were stated Multiple databases (Medline [1946 to 2012], Embase [1974 to 2012], LILACS [1982 to 2012], PsycINFO [1806 to 2012]) were searched. Also, trial registries and reference lists of relevant articles were searched. Study selection was described Flow chart of study selection was provided List of included studies was provided List of excluded studies was provided Article selection was done in duplicate Data extraction was done in duplicate Quality assessment was done using the Cochrane Risk of Bias tool and overall studies were judged to be of limited quality Characteristics of the individual studies were provided. Meta-analyses were conducted when feasible Publication bias was explored using Funnel plot if feasible The authors stated that there were no known conflicts of interest.
|
|
| Clark,5 2014, USA |
|---|
The objective was clearly stated. The inclusion criteria were stated. The exclusion criteria were stated Multiple databases (PubMed [1946 to 2013], Medline 2003 to 2013], Cochrane database of systematic reviews) were searched. Also, trial registries and reference were searched. Study selection was described Flow chart of study selection was provided Article selection was done in duplicate Quality of evidence of the individual studies were judged according to the American College of Physicians guideline grading system (of 2010) and varied between moderate and high Characteristics of the individual studies were provided but lacked details Disclosures were provided by the authors. Of the three authors, one author was associated with industry and the other two authors mentioned that they have no conflicts of interest.
|
List of excluded studies was not provided Unclear if data extraction was done in duplicate Meta-analysis was not conducted, findings of individual studies were presented narratively Unclear if publication bias was explored
|
| Lv,1 2017, China |
|---|
The objective was clearly stated. The inclusion criteria were stated Multiple databases (PubMed, Embase [search dates not mentioned]) were searched. Study selection was described Flow chart of study selection was provided Data extraction was done in duplicate. Characteristics of the individual studies were provided. Network meta-analysis was conducted. A Bayesian framework model was used. Ranking probabilities of the treatments were presented. Results of direct analysis, indirect analysis, and network meta-analysis (NMA) were presented. There were some inconsistencies between direct and indirect comparison results. The direct comparison and NMA results were mostly comparable. Outcomes from each individual study were not reported. There was heterogeneity among the studies with respect to population, NMSC subgroups, lesion size and location, follow-up times. Publication bias was explored using Funnel plots and no issues were apparent. The authors mentioned that there were no conflicts of interest.
|
The exclusion criteria were not explicitly stated List of excluded studies was not provided Unclear if article selection was done in duplicate Unclear if quality assessment of the studies was undertaken
|
Table 6Strengths and Limitations of Randomized Controlled Trials using Downs and Black checklist
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| Strengths | Limitations |
|---|
| Bath-Hextall,10 2014, UK |
|---|
The objective was clearly stated The inclusion and exclusion criteria were stated Patient characteristics, intervention and outcomes were described. Computer generated block randomization. Randomization was stratified center and type of BCC Sample size was calculated and met A modified ITT analysis was done. Modified ITT population was defined as all patients who received at least one application of imiquimod cream or surgery, and for whom the data for the outcome being analyzed were available. Per protocol analysis was also conducted. P values or 98% confidence intervals were reported The authors mentioned that there were no conflicts of interest.
|
Blinding was not possible due to the nature of the interventions. The statistician was blinded to allocation until all the analysis was completed Lost to follow up was unequal in the groups (14% in IMQ, 21% in surgery)
|
| Roozeboom,18 2016, The Netherlands; Roozeboom,9 2015, The Netherlands; Arits,12 2013, The Netherlands |
|---|
The objective was clearly stated The inclusion and exclusion criteria were stated Patient characteristics, intervention and outcomes were described. Computer generated block randomization. Randomization was stratified by age and tumor location. Sample size was calculated and met A modified ITT analysis (including patients with data at 3 and 12 months follow-up) was done. Per protocol analysis was also conducted. P values or 95% confidence intervals were reported The authors mentioned that there were no conflicts of interest.
|
Single-blind study. Follow-up and data collection was done by one physician who was blinded to treatment allocation. Statistical analyses were conducted by two investigators who were blinded to allocation. Lost to follow up and/or not considered in the analyses) were unequal in the groups; they were by 1 year, 22% in MAL-PDT, 14% in IMQ, 15% in FU; and by 3 years 37% in MAK-PDT, 24% in IMQ, 27% in FU.
|
Table 7Strengths and Limitations of Economic Studies using Drummond Checklist
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| Strengths | Limitations |
|---|
| Arits,19 2014, The Netherlands |
|---|
Objectives were stated. The strategies compared were stated. Time horizon (1 year) and perspective (health care perspective) were stated. Clinical data source were stated (data from RCT). Cost data source were stated (such as Dutch manual of costing, Maastricht University Medical Centre data). Cost data were collected alongside the multicenter RCT comparing the three interventions that were assessed in the economic evaluation. There was no discounting necessary as the time horizon was 1 year Incremental analysis was reported. Sensitivity analyses were conducted. Conclusions were consistent with the results reported.
|
Indirect costs were not considered. The analysis considered I year time horizon, hence cost-effectiveness in the long term is unclear.
|
Appendix 4. Main Study Findings and Author’s Conclusions
Table 8Summary of Findings of Included Studies
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| Main Study Findings | Author’s Conclusion |
|---|
| Systematic reviews |
|---|
| Bath-Hextall,8 2013, Cochrane Collaboration |
|---|
For patients with Bowen’s disease (in situ SCC)
Clinical outcomes with IMQ compared to placebo | “There is only limited quality data available to guide clinical practice. [….] Photodynamic therapy appears to be an effective and safe non-scarring treatment, which should be considered if available. The limited data suggest that 5 fluorouracil is as effective as PDT, that cryotherapy is possibly less effective than PDT, and that imiquimod is also effective, but has not been compared with PDT. Cost, likely adverse events, and patient preference will all play a part in the choice of treatment.” Page 20 |
| Outcome | No. of patients with outcome | P value |
|---|
| IMQ (N = 15) | Placebo (N = 16) |
|---|
| Lesion clearance | 9 | 0 | <0.001 |
| Recurrence at 72 week follow-up | 0 | 2 developed early invasive SCC | NR |
Cosmetic outcome:
Often clinical resolution was accompanied with faint residual blanching erythema or post-inflammatory hyperpigmentation, actual numbers were however not available in the trial report.
Adverse events:
Most patients treated with IMQ experienced localized inflammatory reactions. Overall, of the 31 patients, 19 experienced transient itching, edema, or weeping. Four patients experienced treatment related adverse event. |
| Clark,5 2014, USA |
|---|
For patients with BCC
Outcomes with IMQ compared to other therapies | “The available data suggest that surgical methods remain the gold standard in BCC treatment, with Mohs micrographic surgery typically utilized for high-risk lesions. Suitable alternate treatment options for appropriately selected primary low-risk lesions may include PDT, cryotherapy, topical imiquimod, and 5-FU. Radiotherapy is a suitable alternate for surgical methods for treatment in older patient populations.” Page197 |
| Comparison | No. of RCTs | No. of patients | Findings |
|---|
| MAL-PDT vs IMQ (5%) vs FU | 1 | 601 | Recurrence rate: 27.2% for MAL-PDT, 16.6% for IMQ, and 19.9% for FU.FU vs IMQ (P = 0.435;, FU vs MAL-PDT (P = 0.120); and IMQ vs MAL-PDT (P = 0.012), favoring IMQ.
Approximately 60% reported good to excellent cosmetic outcomes in all three groups.
IMQ and FU groups experienced greater frequency of moderate to severe local reactions |
| IMQ(5%) vs RTx | 1 | 27 | Histologic clearance rate: 100% for both groups at 15 weeks
Relapse rate: 0% for both groups at 24 months
Cosmetic outcomes better with IMQ compared to RTx
RTx was associated with loss of eyelashes and dry eye syndrome post-Tx. IMQ was associated with greater adverse events and less tolerability during Tx compared to RTx |
| MMS plus pre-Tx with IMQ (5%) vs MMS plus pre-Tx with vehicle | 1 | 70 | Recurrence rate 0% in both arms at 20 month
Pre-Tx with IMQ reduced post-Mohs defect size to a greater extent compared to pre-Tx with vehicle |
| IMQ (5%) vs vehicle | 1 | 166 | Histologic clearance rate: 80% for IMQ; 6% for vehicle (P<0.001), at 12 weeks
Cosmetic outcomes: With IMQ there was worsening of hypopigmentation but improvement with respect to textural irregularities and dyspigmentation.
Adverse events Common adverse events with IMQ were local and application site reaction but were generally well tolerated, with only 2 patients discontinuing treatment. |
| IMQ (5%) for 5x/week vs IMQ(5%) for 7x/week vs vehicle for 5x/week vs vehicle for 7x/week | 1 | 724 | At 3 months post-Tx, both the IMQ groups had significant composite and histologic clearance compared with vehicle (P <0.001).
At 12 weeks for IMQ, the 5x/week regimen [T1] was preferred over the 7x/week regimen [T2] due to its greater safety and comparable efficacy (T1 vs T2: clinical clearance rate, 75% vs 73%; histologic clearance rate, 82% vs 79%) |
| Lv,1 2017, China |
|---|
For adults with NMSC (BCC, SCC, or BD)
Ranking probabilities and SUCRA | “In conclusion, this NMA identified SE as the optimal regimen for NMSC with high efficacy considering CLR, CLC, and CRP and moderate AEs when compared with other interventions. It provides evidence for the future clinical choice, while efforts still shall be paid to eliminate the heterogeneity and carry out more advanced studies.” Page 9 |
| Outcome | Intervention | Rank 1 | Rank 2 | SUCRA |
|---|
| CLR | CTx | 0.06 | 0.13 | 0.32 |
| IMQ | 0.08 | 0.39 | 0.61 |
| PDT | 0.07 | 0.36 | 0.63 |
| RTx | 0.07 | 0.22 | 0.43 |
| surgery (SE) | 0.71 | 0.89 | 0.91 |
| vehicle | 0.00 | 0.01 | 0.09 |
| CLC | CTx | 0.09 | 0.35 | 0.55 |
| FU | 0.01 | 0.06 | 0.31 |
| IMQ | 0.15 | 0.50 | 0.64 |
| PDT | 0.01 | 0.18 | 0.52 |
| surgery (SE) | 0.74 | 0.90 | 0.91 |
| vehicle | 0.00 | 0.02 | 0.07 |
| CRP | CTx | 0.01 | 0.08 | 0.30 |
| FU | 0.12 | 0.34 | 0.55 |
| IMQ | 0.16 | 0.35 | 0.52 |
| PDT | 0.00 | 0.02 | 0.23 |
| RTx | 0.35 | 0.54 | 0.64 |
| surgery (SE) | 0.35 | 0.66 | 0.76 |
| AE | CTx | 0.49 | 0.84 | 0.85 |
| FU | 0.01 | 0.06 | 0.25 |
| IMQ | 0.00 | 0.03 | 0.22 |
| PDT | 0.00 | 0.04 | 0.32 |
| surgery (SE) | 0.03 | 0.21 | 0.52 |
| vehicle | 0.047 | 0.82 | 0.83 |
| Randomized controlled trials |
|---|
| Bath-Hextall,10 2014, UK; (Williams,17 2017, UK for 5 year follow up data) |
|---|
For adult patients with nodular BCC or superficial BCC
Success rate with IMQ compared to surgery (modified ITT analysis) | “Imiquimod was inferior to surgery according to our predefined non inferiority criterion. Although excisional surgery remains the best treatment for low-risk basal-cell carcinoma, imiquimod cream might still be a useful treatment option for small low-risk superfi cial or nodular basal-cell carcinoma dependent on factors such as patient preference, size and site of the lesion, and whether the patient has more than one lesion.” Page 6, Bath-Hextall et al.10
“Although surgery is clearly superior to imiquimod, this study shows sustained benefit for lesions that respond early to topical imiquimod.” Page 614, Williams et al.17 |
| Time period (year) | BCC type | Proportion successfully treated, n/N (%) | RR (98% CI) | P valuea |
|---|
| IMQ | Surgery |
|---|
| 1 | Superficial | 106/119
(89.1%) | 99/100
(99.0%) | NR | NR |
| Nodular | 95/111
(85.6%) | 98/99
(99.0%) | NR | NR |
| All | 201/230
(87.4%) | 197/199
(99.0%) | 0.88 (0.82-0.93) | <0.0001 |
| 2 | Superficial | 101/116
(87.1%) | 99/100
(99.0%) | NR | NR |
| Nodular | 90/107
(84.1%) | 92/93
(98.9%) | NR | NR |
| All | 191/223
(85.7%) | 191/193
(99.0%) | 0.86 (0.80-0.92) | <0.0001 |
| 3 | Superficial | 97/114
(85.1%) | 96/98
(98.0%) | NR | NR |
| Nodular | 81/99
(81.8%) | 89/90
(98.9%) | NR | NR |
| All | 178/213
(83.6%) | 185/188
(98.4%) | 0.84 (078-0.91) | <0.0001 |
aFrom likelihood ratio test
Note: The pre-specified non-inferiority margin was a relative risk (RR) of 0.87, i.e. IMQ was considered to be non-inferior to surgery if lower limit of RR > 0.87 |
| Success rate with IMQ compared to surgery (per protocol analysis) |
| Time period (year) | BCC type | Proportion successfully treated | RR (98% CI) | P valuea |
|---|
| IMQ | Surgery |
|---|
| 3 | Superficial | 92/109
(84.4%) | 96/98
(98.0%) | NR | NR |
| Nodular | 76/93
(81.7%) | 88/89
(98.9%) | NR | NR |
| All | 168/202
(83.2%) | 184/187
(98.4%) | 0.83 (0.77-0.90) | <0.0001 |
| aFrom likelihood ratio test |
| Cosmetic appearance (excellent or good) with IMQ compared to surgery |
| Time period | BCC type | Proportion of patients successfully treated, n/N (%) | RR (98% CI) | P valuea |
|---|
| IMQ | Surgery |
|---|
| 6 month | Superficial | 33/112
(29.5%) | 10/99
(10.1%) | NR | NR |
| Nodular | 41/101
(40.6%) | 22/96
(22.9%) | NR | NR |
| All | 74/213
(34.7%) | 32/195
(16.4%) | 2.15 (1.43 to 3.23) | <0.0001 |
| 2 years | Superficial | 62/93
(66.7%) | 29/89
(32.6%) | NR | NR |
| Nodular | 41/77
(53.3%) | 33/85
(38.8%) | NR | NR |
| All | 103/170
(60.6%) | 62/174
(35.6%) | 1.79 (1.36-2.36) | <0.0001 |
| aFrom likelihood ratio test |
| Pain with IMQ compared to surgery, during treatment |
| BCC type | Pain intensity | Proportion0f patients experiencing pain, n/N (%) |
|---|
| IMQ | Surgery |
|---|
| Superficial | No pain | 44/122 (36%) | 35/101 (35%) |
| Mild, mild to moderate | 45/122 (37%) | 44/101 (44%) |
| Moderate, moderate to severe, severe | 33/122 (27%) | 22/101 (22%) |
| Nodular | No pain | 29/120 (24%) | 27/100 (27%) |
| Mild, mild to moderate | 52/120 (43%) | 51/100 (51%) |
| Moderate, moderate to severe, severe | 39/120 (33%) | 22/100 (22%) |
| All | No pain | 73/242 (30%) | 62/201 (31%) |
| Mild, mild to moderate | 97/242 (40%) | 95/201 (47%) |
| Moderate, moderate to severe, severe | 72/242 (30%) | 44/201 (22%) |
| Pain was recorded in daily diaries; data were missing for some patients |
| Pain with IMQ compared to surgery, 16 weeks after treatment |
| BCC type | Pain intensity | Proportion of patients experiencing pain, n/N (%) |
|---|
| IMQ | Surgery |
|---|
| Superficial | No pain | 63/122 (52%) | 25/103 (24%) |
| Mild, mild to moderate | 46/122 (38%) | 54/103 (52%) |
| Moderate, moderate to severe, severe | 13/122 (11%) | 24/103 (23%) |
| Nodular | No pain | 72/111 (65%) | 30/103 (29%) |
| Mild, mild to moderate | 30/111 (27%) | 56/103 (54%) |
| Moderate, moderate to severe, severe | 9/111 (8%) | 17/103 (17%) |
| All | No pain | 135/233 (58%) | 55/206 (27%) |
| Mild, mild to moderate | 76/233 (33%) | 110/206 (53%) |
| Moderate, moderate to severe, severe | 22/233 (9%) | 41/206 (20%) |
| Pain was recorded in daily diaries; data were missing for some patients |
| Adverse events with IMQ compared to surgery |
| Adverse event (AE) | BCC type | Proportion of patients with AE, n/N (%) |
|---|
| IMQ | Surgery |
|---|
| AE in the first 6 months | Superficial | 120/128 (94%) | 105/114 (92%) |
| Nodular | 120/126 (95 | %) 97/115 (84%) |
| All | 240/254 (94%) | 202/229 (88%) |
| AE during trial (up to 3 years) | Superficial | 121/128 (95%) | 107/114 (94%) |
| Nodular | 121/126 (96%) | 101/115 (88%) |
| All | 242/254 (95%) | 208/229 (91%) |
| Serious adverse eventa | Superficial | 52/128 (41%) | 60/114 (53%) |
| Nodular | 47/126 (37%) | 37/115 (32%) |
| All | 99/254 (39%) | 97/229 (42%) |
| aNo serious adverse event was treatment related |
| Success rate with IMQ compared to surgery (modified ITT analysis) at 5 year follow up |
| Time period (year) | BCC type | Proportion successfully treated, n/N (%) | RR (98% CI) | P valuea |
|---|
| IMQ | Surgery |
|---|
| 5 | Superficial | 93/111 (83.8) | 91/94
(96.8) | NR | NR |
| Nodular | 77/95 (81.1) | 82/83
(98.8) | NR | NR |
| All | 170/206
(82.5) | 173/177
(97.7) | 0.84 (0.77 to
0.91) | <0.0001 |
aFrom likelihood ratio test
Note: IMQ was considered to be non-inferior to surgery if lower limit of RR > 0.87 |
| Roozeboom,18 2016, Roozeboom,9 2015, Arits,12 2013; The Netherlands |
|---|
For patients with sBCC
Cumulative probability of tumor free survival (modified ITT analysis) | “Topical fluorouracil was non-inferior and imiquimod was superior to MAL-PDT for treatment of superficial basal-cell carcinoma. On the basis of these findings, imiquimod can be considered the preferred treatment, but all aspects affecting treatment choice should be weighted to select the best treatment for patients.” Page 647, Arits12 2013
“In order patients with sBCC on the lower extremities MAL-PDT might be preferred. Results should be interpreted carefully as subgroup analyses were exploratory and not driven by prior hypotheses.” Page 739, Roozeboom9 2015 |
| Intervention | Cumulative probability (% )of tumor free survival at post treatment |
|---|
| 1 year | 3 years |
|---|
| MAL-PDT | 72.8 (66.8 to 79.4) | 58.0 (47.8 to 66.9) |
| IMQ | 83.4 (78.2 to 88.9) | 79.7 (71.6 to 85.7) |
| FU | 80.1 (74.7 to 85.9) | 68.2 (58.1 to 76.3) |
| The results were similar for per protocol analysis |
| Comparison of tumor free survival between the interventions at 3 years (modified ITT analysis) |
| Interventions compared | Absolute difference (%) | HR (95% CI)a |
|---|
| IMQ versus MAL-PDT | 21.7 | 0.50 (0.33 to 0.76) |
| FU versus MAL-PDT | 10.2 | 0.73 (0.51 to 1.05) |
| FU versus IMQ | -11.5 | 0.68 (0.44 to 1.06) |
| aTo test if IMQ or FU was not inferior to treatment with MAL-PDT, a pre-specified non-inferiority margin of 10% for absolute difference in survival was used. This translated to non-inferiority of FU or IMQ in comparison to MAL-PDT if the corresponding HR had a 95% CI entirely below 1.35 and superiority if the corresponding HR had a 95% CI entirely below 1.00. |
| Treatment success for various subgroups of patients |
| Category | Subgroup | Proportion (%) with treatment success | Between group difference (95% CI) | P value |
|---|
| MAL-PDT (N = 196) | IMQ (N = 189) |
|---|
| Gender | Male | 75.36 | 77.3 | 2.0 (-10.1 to 14.1) | 0.746 |
| Female | 71.8 | 90.2 | 18.4 (7.8 to 29.0) | 0.001 |
| Age | ≤; 60 years | 69.1 | 89.6 | 20.5 (8.3 to 32.7) | 0.002 |
| > 60 years | 76.5 | 79.5 | 3.0 (-7.7 to 13.7) | 0.586 |
| Tumor location | Head/neck | 62.5 | 80.0 | 17.5 (-9.3 to 43.6 | 0.205 |
| Upper extremities | 83.9 | 88.0 | 4.1 (-14.1 to 22.2) | 0.663 |
| Lower extremities | 92.3 | 57.1 | -35.2 (-56.2 (-14.2) | 0.003 |
| Trunk | 68.7 | 89.7 | 21.0 (10.9 to 31.1) | <0.001 |
| Tumor sizea | ≤ 60 mm2 | 78.3 | 80.0 | 1.7 (-9.7 to 13.1) | 0.771 |
| > 60 mm2 | 68.6 | 87.5 | 18.9 (7.1 to 30.7) | 0.002 |
| aFor tumor size, data were available for 192 patients in MAL-PDT group and 186 in IMQ group |
| Treatment success for various subgroups of patients with sBCC located on lower extremities |
| Category | Subgroup | Proportion (%) with treatment success | Between group difference (95% CI) | P value |
|---|
| MAL-PDT (N = 25) | IMQ (N = 28) |
|---|
| Gender | Male | 100.0 | 46.7 | -53.3 (-79.0 to -28.1) | 0.090 |
| Female | 90.9 | 69.2 | -21.7 (-49.5 to 6.1) | 0.100 |
| Age | ≤ 60 years | 87.5 | 100.0 | 12.5 (-10.4 to 35.4) | 0.274 |
| > 60 years | 94.1 | 36.8 | -57.3 (-81.7 to -32.9) | <0.001 |
| Tumor size | ≤ 60 mm2 | 89.5 | 60.0 | -29.5 (-57.9 to -1.1) | 0.044 |
| > 60 mm2 | 100.0 | 54.5 | -45.5 (-74.9 to -16.1) | 0.049 |
Aesthetic outcomes
Proportions of patients reporting good to excellent aesthetic outcomes were 62.4% for MAL-PDT group, 61.4% for IMQ group and 57.5% for FU group; between group differences were not statistically significant.
Compliance
Compliance in the MAL-PDT group was 100%; 20.9% in the IMQ group and 31.3% in the FU group had less than 100% compliance.
Adverse events
Moderate or severe local skin redness was reported in all the groups. IMQ and FU groups more often reported moderate to severe local swelling, erosion, crust formation and itching compared to the MAL-PDT group. Unexpected serious adverse effects were reported by 4.8% in the IMQ group, 2.1% in the FU group and by none in the MAL-PDT group. |
| Economic studies |
|---|
| Arits,19 2014, The Netherlands |
|---|
For patients with sBCC
Base case analysis: | “Based on the 12 months follow-up results, imiquimod and topical fluorouracil cream are more cost-effective than MALPDT for treatment of sBCC. Hence, substituting MAL-PDT with either imiquimod or topical fluorouracil results in cost savings; these savings will be larger for topical fluorouracil. Long term followup effectiveness data are necessary to confirm the cost-effectiveness of imiquimod vs. topical 5-fluorouracil cream.” Page 1 |
| Treatment ( or treatment difference) | Costa (€) | Effectivenessb | ICER |
|---|
| MAL-PDT | 680 | 0.728 | NA |
| IMQ | 526 | 0.831 | NA |
| (MAL-PDT) - IMQ | 154 | -0.103 | IMQ dominantc |
| IMQ | 526 | 0.831 | NA |
| FU | 388 | 0.800 | NA |
| IMQ- FU | 138 | 0.031 | €4451 for IMQ compared to FU |
| MAL-PDT | 680 | 0.728 | NA |
| FU | 388 | 0.800 | NA |
| (MAL-PDT) - FU | 292 | -0.072 | NA |
a The significantly higher treatment costs for MAL-PDT compared with imiquimod cream were mainly attributable to overhead costs and personnel costs. The significantly higher cost-difference of MAL-PDT vs. topical fluorouracil cream was a consequence of the higher cost of the Metvix cream, and overhead and personnel costs. The significantly higher treatment costs for imiquimod compared with topical fluorouracil were due to higher costs of the imiquimod cream.” Page 4.
bEffectiveness assessed as success (no tumor residue or no recurrence) rate.
cDominant: more effective and less cost. |
| Univariate sensitivity analysis with MAL-PDT treatment cost reduced (by reducing Metvix cream treatment cost) |
| Treatment ( or treatment difference) | Costa (€) | Effectivenessb | ICER |
|---|
| MAL-PDT | 583 | 0.728 | NA |
| IMQ | 526 | 0.831 | NA |
| (MAL-PDT) - IMQ | 57 | -0.103 | IMQ dominantc |
| IMQ | 526 | 0.831 | NA |
| FU | 388 | 0.800 | NA |
| IMQ- FU | 138 | 0.031 | €4451 for IMQ compared to FU |
| MAL-PDT | 583 | 0.728 | NA |
| FU | 388 | 0.800 | NA |
| (MAL-PDT) - FU | 195 | -0.072 | FU dominantc |
a” The significantly higher treatment costs for MAL-PDT compared with imiquimod cream were mainly attributable to overhead costs and personnel costs. The significantly higher cost-difference of MAL-PDT vs. topical fluorouracil cream was a consequence of the higher cost of the Metvix cream, and overhead and personnel costs. The significantly higher treatment costs for imiquimod compared with topical fluorouracil were due to higher costs of the imiquimod cream.” Page 4.
bEffectiveness assessed as success (no tumor residue or no recurrence) rate.
cDominant: more effective and less cost. |
| Univariate sensitivity analysis with IMQ treatment cost reduced (30 sachets instead of 36 sachets used in the base case) |
| Treatment ( or treatment difference) | Costa (€) | Effectivenessb | ICER |
|---|
| MAL-PDT | 680 | 0.728 | NA |
| IMQ | 495 | 0.831 | NA |
| (MAL-PDT) - IMQ | 185 | -0.103 | IMQ dominantc |
| IMQ | 495 | 0.831 | NA |
| FU | 388 | 0.800 | NA |
| IMQ- FU | 107 | 0.031 | €3451 for IMQ compared to FU |
| MAL-PDT | 680 | 0.728 | NA |
| FU | 388 | 0.800 | NA |
| (MAL-PDT) - FU | 292 | -0.072 | FU dominantc |
a The significantly higher treatment costs for MAL-PDT compared with imiquimod cream were mainly attributable to overhead costs and personnel costs. The significantly higher cost-difference of MAL-PDT vs. topical fluorouracil cream was a consequence of the higher cost of the Metvix cream, and overhead and personnel costs. The significantly higher treatment costs for imiquimod compared with topical fluorouracil were due to higher costs of the imiquimod cream.” Page 4.
bEffectiveness assessed as success (no tumor residue or no recurrence) rate.
cDominant: more effective and less cost. |
AE = adverse event; BCC = basal cell carcinoma; CI =confidence interval; CLC = complete lesion clearance; CLR = complete lesion response; CRP = cumulative recurrence probability; CTx = cryotherapy; FU = fluorouracil; HR = hazard ratio; ICER = incremental cost-effectiveness ratio; IMQ = imiquimod; ITT = intention-to-treat; MAL-PDT = methylaminolevulinate photodynamic therapy; NA = not applicable; NMA = network meta-analysis; NR = not reported; PDT = photodynamic therapy; RR = relative risk; RTx = radiotherapy; sBCC = superficial basal cell carcinoma; SCC = squamous cell carcinoma; SUCRA = surface under the cumulative ranking curve; Tx = treatment; vs = versus.
About the Series
CADTH Rapid Response Report: Summary with Critical Appraisal
Suggested citation:
Imiquimod for the treatment of basal cell or squamous carcinoma: a review of clinical effectiveness and cost-effectiveness. Ottawa: CADTH; 2017 Sept. (CADTH rapid response report: summary with critical appraisal).
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