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Three-Year Follow-Up Results of Photodynamic Therapy vs. Imiquimod vs. Fluorouracil for Treatment of Superficial Basal Cell Carcinoma: A Single-Blind, Noninferiority, Randomized Controlled Trial

  • Marieke H. Roozeboom
    Correspondence
    Correspondence: Marieke H. Roozeboom, Department of Dermatology, Maastricht University Medical Centre, P. Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
    Affiliations
    Department of Dermatology, Maastricht University Medical Centre, Maastricht, The Netherlands

    GROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
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  • Aimee H.M.M. Arits
    Affiliations
    Department of Dermatology, Maastricht University Medical Centre, Maastricht, The Netherlands

    GROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands

    Department of Dermatology, Catharina Hospital, Eindhoven, The Netherlands
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  • Klara Mosterd
    Affiliations
    Department of Dermatology, Maastricht University Medical Centre, Maastricht, The Netherlands

    GROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
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  • Anja Sommer
    Affiliations
    Department of Dermatology, Dermatology Clinic, Maastricht, The Netherlands
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  • Brigitte A.B. Essers
    Affiliations
    Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht, The Netherlands
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  • Michette J.M. de Rooij
    Affiliations
    Department of Dermatology, VieCuri Medical Centre, Venlo, The Netherlands
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  • Patricia J.F. Quaedvlieg
    Affiliations
    Department of Dermatology, Zuyderland Medical Centre, Heerlen, The Netherlands
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  • Peter M. Steijlen
    Affiliations
    Department of Dermatology, Maastricht University Medical Centre, Maastricht, The Netherlands

    GROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands

    Department of Dermatology, Catharina Hospital, Eindhoven, The Netherlands
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  • Author Footnotes
    9 These authors contributed equally to this work.
    Patty J. Nelemans
    Footnotes
    9 These authors contributed equally to this work.
    Affiliations
    Department of Epidemiology, Maastricht University, Maastricht, The Netherlands
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  • Author Footnotes
    9 These authors contributed equally to this work.
    Nicole W.J. Kelleners-Smeets
    Footnotes
    9 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Maastricht University Medical Centre, Maastricht, The Netherlands

    GROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
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  • Author Footnotes
    9 These authors contributed equally to this work.
Open ArchivePublished:April 22, 2016DOI:https://doi.org/10.1016/j.jid.2016.03.043
      A randomized controlled trial including 601 patients previously showed that the effectiveness of imiquimod and fluorouracil cream were not inferior to methyl aminolevulinate photodynamic therapy (MAL-PDT) in patients with superficial basal cell carcinoma after 1 year of follow-up. We now present the 3-year follow-up results. The probability of tumor-free survival at 3 years post-treatment was 58.0% for MAL-PDT (95% confidence interval [CI] = 47.8–66.9), 79.7% for imiquimod (95% CI = 71.6–85.7), and 68.2% for fluorouracil (95% CI = 58.1–76.3). The hazard ratio for treatment failure comparing imiquimod with MAL-PDT was 0.50 (95% CI = 0.33–0.76, P = 0.001). Comparison of fluorouracil with MAL-PDT and fluorouracil with imiquimod showed hazard ratios of 0.73 (95% CI = 0.51–1.05, P = 0.092) and 0.68 (95% CI = 0.44–1.06, P = 0.091), respectively. Subgroup analysis showed a higher probability of treatment success for imiquimod versus MAL-PDT in all subgroups with the exception of elderly patients with superficial basal cell carcinoma on the lower extremities. In this subgroup, the risk difference in tumor-free survival was 57.6% in favor of MAL-PDT. In conclusion, according to results at 3 years post-treatment, imiquimod is superior and fluorouracil not inferior to MAL-PDT in treatment of superficial basal cell carcinoma.

      Abbreviations:

      BCC (basal cell carcinoma), CI (confidence interval), HR (hazard ratio), MAL (methyl aminolevulinate), PDT (photodynamic therapy), sBCC (superficial basal cell carcinoma)

      Introduction

      Basal cell carcinoma (BCC) is the most common type of skin cancer, and its increasing incidence puts a large burden on health care services worldwide (
      • Flohil S.C.
      • Seubring I.
      • van Rossum M.M.
      • Coebergh J.W.
      • de Vries E.
      • Nijsten T.
      Trends in basal cell carcinoma incidence rates: a 37-year Dutch observational study.
      ,
      • Lomas A.
      • Leonardi-Bee J.
      • Bath-Hextall F.
      A systematic review of worldwide incidence of non-melanoma skin cancer.
      ,
      • van der Geer S.
      • Reijers H.A.
      • van Tuijl H.F.
      • de Vries H.
      • Krekels G.A.
      Need for a new skin cancer management strategy.
      ). BCC can be categorized into three main histological subtypes: superficial, nodular, and aggressive (
      • Rippey J.J.
      Why classify basal cell carcinomas?.
      ). Although most subtypes require surgery, superficial BCC (sBCC) can also be treated topically with alternatives such as photodynamic therapy (PDT), imiquimod cream, fluorouracil cream, cryosurgery, or electrodessication and curettage (
      • Trakatelli M.
      • Morton C.
      • Nagore E.
      • Ulrich C.
      • Del Marmol V.
      • Peris K.
      • et al.
      Update of the European guidelines for basal cell carcinoma management.
      ). The main advantages of noninvasive treatments like PDT, imiquimod, and fluorouracil are good cosmetic outcome, preservation of surrounding tissue, and potential for home application of both creams (
      • Szeimies R.M.
      • Ibbotson S.
      • Murrell D.F.
      • Rubel D.
      • Frambach Y.
      • de Berker D.
      • et al.
      A clinical study comparing methyl aminolevulinate photodynamic therapy and surgery in small superficial basal cell carcinoma (8-20 mm), with a 12-month follow-up.
      ,
      • Trakatelli M.
      • Morton C.
      • Nagore E.
      • Ulrich C.
      • Del Marmol V.
      • Peris K.
      • et al.
      Update of the European guidelines for basal cell carcinoma management.
      ). However, to date there is a lack of randomized controlled trials with long-term follow-up periods that compare effectiveness of noninvasive treatment modalities (
      • Roozeboom M.H.
      • Arits A.H.
      • Nelemans P.J.
      • Kelleners-Smeets N.W.
      Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.
      ). Therefore, in international BCC guidelines, no consensus has been reached on the first choice of noninvasive therapy for sBCC (
      • Trakatelli M.
      • Morton C.
      • Nagore E.
      • Ulrich C.
      • Del Marmol V.
      • Peris K.
      • et al.
      Update of the European guidelines for basal cell carcinoma management.
      ).
      To assess the effectiveness of imiquimod and fluorouracil versus methyl aminolevulinate photodynamic therapy (MAL-PDT) for treatment of sBCC, a randomized controlled trial was conducted. The 1-year follow-up results of this noninferiority study showed that imiquimod was superior and fluorouracil not inferior to MAL-PDT (
      • Arits A.H.
      • Mosterd K.
      • Essers B.A.
      • Spoorenberg E.
      • Sommer A.
      • De Rooij M.J.
      • et al.
      Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
      ). Because long-term follow-up studies are lacking and sBCC may recur between 1 and 3 years post-treatment, a longer follow-up period is required to evaluate the sustained treatment success (
      • Christensen E.
      • Mork C.
      • Skogvoll E.
      High and sustained efficacy after two sessions of topical 5-aminolaevulinic acid photodynamic therapy for basal cell carcinoma: a prospective, clinical and histological 10-year follow-up study.
      ,
      • Quirk C.
      • Gebauer K.
      • De'Ambrosis B.
      • Slade H.B.
      • Meng T.C.
      Sustained clearance of superficial basal cell carcinomas treated with imiquimod cream 5%: results of a prospective 5-year study.
      ,
      • Roozeboom M.H.
      • Arits A.H.
      • Nelemans P.J.
      • Kelleners-Smeets N.W.
      Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.
      ). We now report the 3-year follow-up results of this study. In addition, we have performed exploratory (not driven by prior hypotheses) subgroup analysis within this noninferiority trial at 3 years of follow-up.

      Results

      Patients

      A total of 601 patients were randomized to receive MAL-PDT (n = 202), imiquimod (n = 198), or fluorouracil (n = 201). The three study groups had a similar distribution of baseline characteristics, except for tumor size (Table 1). The mean tumor size treated with MAL-PDT was smaller than the mean size in both the imiquimod and fluorouracil groups. Of the 601 enrolled patients, 590 started treatment (Figure 1). Eleven patients did not start treatment because they refused, withdrew, died, or were unresponsive to telephone calls. After randomization, five cross-overs occurred before the assigned treatment was started because these patients had a strong preference for a different treatment group. One patient did not receive the allocated MAL-PDT but was treated with imiquimod, and one patient allocated to imiquimod and three patients allocated to fluorouracil received MAL-PDT. No treatment failures occurred between the 3-month and 1-year follow-up visits. During follow-up, protocol deviations occurred in four patients when the treating physician decided that there was a need for extra treatment because of clinical suspicion of tumor recurrence: surgical excision in two patients and noninvasive treatment in two patients. No histological evidence of tumor recurrence was found in the excised specimens, and no histological verification was available for the patients treated with MAL-PDT. Because these four patients could not be further assessed for recurrence during follow-up, they were considered as lost to follow-up (Figure 1).
      Table 1Distribution of patient and tumor characteristics
      CharacteristicMAL-PDT (n = 202)Imiquimod cream (n = 198)Fluorouracil cream (n = 201)
      Sex, M/F96/106102/96106/95
      Median age in years (range)63 (26–87)62 (30–91)64 (35–86)
      Tumor location, n (%)
       Head/neck24 (12)23 (12)31 (15)
       Trunk119 (59)121 (61)120 (60)
       Upper extremities32 (16)26 (13)27 (13)
       Lower extremities27 (13)28 (14)23 (11)
      Median tumor size in mm2 (range)52 (5–1,382)63 (5–1,413)63 (9–5,472)
      Abbreviations: F, female; M, male; MAL-PDT, methyl aminolevulinate photodynamic therapy.
      Figure 1
      Figure 1Flow chart. No treatment failures occurred between the 3-month and 1-year follow-up visits. Surgical excision was done in two patients because of a strong clinical suspicion of recurrence. Because these patients could not be assessed for recurrence during follow-up, they were considered lost to follow-up. ∗∗Noninvasive treatments were given in two patients because of a strong clinical suspicion of recurrence. Because these patients could not be assessed for recurrence of the primary noninvasive treatment during follow-up, they were considered lost to follow-up.
      At the end of the follow-up period, data were missing for 43 patients (7.4%) who were lost to follow-up (7 patients at 3 months, 19 patients at 1 year, and 17 patients at 3 years). Three years post-treatment, 66 patients treated with MAL-PDT, 34 patients treated with imiquimod, and 50 patients treated with fluorouracil had a treatment failure (Figure 1). Twenty-nine treatment failures (15 PDT, 3 imiquimod, 11 fluorouracil) were diagnosed after more than 1 year of follow-up. The median follow-up period in the study was 35 months (range = 1–54 months).

      Probability of tumor-free survival

      Estimates of the 1-year and 3-year cumulative probability of tumor-free survival are presented in Table 2. According to the intention-to-treat analysis, the probability of tumor-free survival at 3 years was 58.0% for MAL-PDT (95% confidence interval [CI] = 47.8–66.9), 79.7% for imiquimod (95% CI = 71.6–85.7), and 68.2% for fluorouracil (95% CI = 58.1–76.3). Based on an estimated 3-year tumor-free survival probability of 58% for the MAL-PDT group, the noninferiority margin of 10% for absolute differences in survival probability translates to a noninferiority threshold for the hazard ratio (HR) of 1.35 (log 0.48/log 0.58) (
      • Com-Nougue C.
      • Rodary C.
      • Patte C.
      How to establish equivalence when data are censored: a randomized trial of treatments for B non-Hodgkin lymphoma.
      ). Consequently, noninferiority of both creams to MAL-PDT can be concluded if the 95% CI of the corresponding HRs are entirely below 1.35. Superiority of both creams to MAL-PDT can be concluded if the 95% CI of the corresponding HRs are entirely below 1.0. Based on an estimated 3-year tumor-free survival probability of 79.7% for imiquimod, the noninferiority margin of 10% for absolute differences in survival probability between imiquimod and fluorouracil translates to a noninferiority threshold for the HR of 1.59 (log 0.697/log 0.797). Superiority of imiquimod to fluorouracil can be concluded if the 95% CI of the corresponding HRs are entirely below 1.0.
      Table 2Cumulative probability of tumor-free survival at 1 and 3 years post-treatment
      Data are reported as % (95% confidence interval).
      1 year3 years
      ITTPPITTPP
      MAL-PDT72.8 (66.8–79.4)72.8 (65.9–78.6)58.0 (47.8–66.9)58.3 (48.3–67.1)
      Imiquimod83.4 (78.2–88.9)83.4 (78.2–88.9)79.7 (71.6–85.7)79.7 (71.6–85.7)
      Fluorouracil80.1 (74.7–85.9)79.5 (73.1–84.6)68.2 (58.1–76.3)68.1 (57.8–76.4)
      Abbreviations: ITT, intention to treat; MAL-PDT, methyl aminolevulinate photodynamic therapy; PP, per protocol.
      1 Data are reported as % (95% confidence interval).
      At 3 years post-treatment, the HR for treatment failure comparing imiquimod with MAL-PDT was 0.50 (95% CI = 0.33–0.76, P = 0.001) (Table 3). Comparison of fluorouracil with MAL-PDT resulted in an HR of 0.73 (95% CI = 0.51–1.05, P = 0.092), and comparison of fluorouracil with imiquimod in an HR of 0.68 (95% CI = 0.44–1.06, P = 0.091).
      Table 3Absolute differences and hazard ratios with 95% confidence intervals of tumor-free survival at 3-year follow-up
      Intention-to-Treat AnalysisPer-Protocol Analysis
      Difference (%)HR (95% CI)PDifference (%)HR (95% CI)P
      Imiquimod vs. MAL-PDT21.70.50 (0.33–0.76)0.00121.40.50 (0.33–0.76)0.001
      Fluorouracil vs. MAL-PDT10.20.73 (0.51–1.05)0.0929.80.73 (0.51–1.06)0.095
      Fluorouracil vs. imiquimod–11.50.68 (0.44–1.06)0.091–11.60.69 (0.44–1.06)0.095
      Abbreviations: CI, confidence interval; HR, hazard ratio; MAL-PDT, methyl aminolevulinate photodynamic therapy.
      These results were nearly identical for the per-protocol analysis: imiquimod compared with MAL-PDT showed an HR of 0.50 (95% CI = 0.33–0.76, P = 0.001), fluorouracil compared with MAL-PDT showed an HR of 0.73 (95% CI = 0.51–1.06, P = 0.095), and fluorouracil with imiquimod showed an HR of 0.69 (95% CI = 0.44–1.06, P = 0.095) (Table 3).

      Subgroup analysis for treatment success

      The relative effect of imiquimod versus MAL-PDT was dependent on age, sex, localization, and sBCC size. Imiquimod was superior to MAL-PDT in the subgroups of women, patients aged 60 years or younger, sBCC on the head/neck and trunk, and tumors larger than 60 mm2 (Table 4). In the other subgroups, imiquimod was also associated with a higher probability of treatment success (but no superiority). An exception was found for the subgroup of sBCC localized to the lower extremities, where a significantly lower probability of treatment success for imiquimod versus MAL-PDT was found, with a difference in success favoring MAL-PDT by 25.2% (HR = 2.07, 95% CI = 0.94 – 4.57, P = 0.070). This finding was further explored by stratifying patients with sBCC on the lower extremities by age (≤60 years vs. >60 years). Within the subgroup of older patients with sBCC on the lower extremities, the 3-year tumor-free survival rate was lower after imiquimod (36.2%) than after MAL-PDT treatment (93.8%). Within the subgroup of younger patients, treatment success was observed in 100% for imiquimod compared with 55.6% for MAL-PDT.
      Table 4Cumulative probability of tumor-free survival, between-group differences, and hazard ratios with 95% confidence intervals at 3 years post-treatment
      P-values in bold reached the noninferiority threshold of the hazard ratio.
      CharacteristicCumulative Probabilities of Treatment Success, % (95% CI)Difference (%)HR (95% CI)
      PDT (n = 196)Imiquimod (n = 189)Imiquimod vs. MAL-PDTImiquimod vs. MAL-PDTp
      Sex
       Male57.6 (41.5–70.8)74.2 (64.0–82.0)16.60.94 (0.58–1.52)0.786
       Female58.4 (45.1–69.6)85.4 (70.8–93.1)27.00.30 (0.16–0.59)<0.001
      Interaction P = 0.029
      Age
       ≤60 years51.0 (35.3–64.7)86.6 (76.5–92.5)35.60.30 (0.15–0.58)<0.001
       >60 years63.8 (50.7–74.3)75.0 (62.8–83.7)11.20.90 (0.56–1.46)0.677
      Interaction P = 0.049
      Tumor location
       Head/neck49.7 (28.7–67.6)79.2 (53.5–91.6)29.50.42 (0.15–1.22)0.112
       Upper extremities71.5 (48.8–85.5)75.0 (39.3–91.5)3.50.73 (0.23–2.25)0.578
       Lower extremities81.2 (56.0–92.8)56.0 (35.5–72.3)–25.22.07 (0.94–4.57)0.070
       Trunk52.1 (37.8–64.5)87.6 (79.9–92.4)35.50.38 (0.21–0.67)0.001
      Interaction P = 0.001
      Tumor size
      Data on tumor size were available in 192 of 196 superficial basal cell carcinomas treated with MAL-PDT and in 186 of 189 superficial basal cell carcinomas treated with imiquimod.
       ≤60 mm260.7 (47.1–71.9)74.4 (60.0–84.3)13.70.77 (0.46–1.30)0.323
       >60 mm254.9 (39.7–67.7)84.1 (75.1–90.1)29.20.43 (0.24–0.77)0.005
      Interaction P = 0.84a
      Abbreviations: CI, confidence interval; HR, hazard ratio; MAL-PDT, methyl aminolevulinate photodynamic therapy.
      1 P-values in bold reached the noninferiority threshold of the hazard ratio.
      2 Data on tumor size were available in 192 of 196 superficial basal cell carcinomas treated with MAL-PDT and in 186 of 189 superficial basal cell carcinomas treated with imiquimod.

      Discussion

      Our results show that imiquimod is superior and fluorouracil not inferior to MAL-PDT in treatment of sBCC after 3 years of follow-up. The finding that around 80% of patients with sBCC are tumor free after imiquimod treatment at 3 years of follow-up is in accordance with results from previous studies. A recent randomized controlled trial by
      • Bath-Hextall F.
      • Ozolins M.
      • Armstrong S.J.
      • Colver G.B.
      • Perkins W.
      • Miller P.S.
      • et al.
      Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial.
      , which compared surgical excision with imiquimod, found that imiquimod was successful in 85.1% of patients with sBCC at 3 years post-treatment. Two other studies reported 3-year cumulative probabilities of tumor-free survival of 82% and 85% (
      • Gollnick H.
      • Barona C.G.
      • Frank R.G.
      • Ruzicka T.
      • Megahed M.
      • Maus J.
      • et al.
      Recurrence rate of superficial basal cell carcinoma following treatment with imiquimod 5% cream: conclusion of a 5-year long-term follow-up study in Europe.
      ,
      • Quirk C.
      • Gebauer K.
      • De'Ambrosis B.
      • Slade H.B.
      • Meng T.C.
      Sustained clearance of superficial basal cell carcinomas treated with imiquimod cream 5%: results of a prospective 5-year study.
      ). This study addresses the probability of tumor-free survival 3 years after MAL-PDT treatment was 58.0%. To our knowledge, only one other randomized controlled trial of MAL-PDT with at least 3 years of follow-up has been performed to enable comparison of results (
      • Basset-Seguin N.
      • Ibbotson S.H.
      • Emtestam L.
      • Tarstedt M.
      • Morton C.
      • Maroti M.
      • et al.
      Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial.
      ). That study included 114 histologically proven primary sBCCs that were treated with one or two MAL-PDT cycles. Results showed a higher cumulative probability of tumor-free survival of 70% at 3 years after MAL-PDT treatment, which may be explained by the fact that incomplete responders received two further MAL-PDT sessions (n = 20) 3 months after the first treatment. In our study, sBCCs were treated with the most current European protocol for MAL-PDT: one MAL-PDT cycle consisting of two treatments with a 1-week interval (
      • Braathen L.R.
      • Szeimies R.M.
      • Basset-Seguin N.
      • Bissonnette R.
      • Foley P.
      • Pariser D.
      • et al.
      Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology.
      ). Incomplete or nonresponders were not retreated. Although a second treatment in the case of a nonresponder 3 months post-treatment might increase tumor-free survival (
      • Roozeboom M.H.
      • Arits A.H.
      • Nelemans P.J.
      • Kelleners-Smeets N.W.
      Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.
      ), a second PDT cycle will further increase the already high treatment costs and require two additional patient visits (
      • Arits A.H.
      • Spoorenberg E.
      • Mosterd K.
      • Nelemans P.
      • Kelleners-Smeets N.W.
      • Essers B.A.
      Cost-effectiveness of topical imiquimod and fluorouracil vs. photodynamic therapy for treatment of superficial basal-cell carcinoma.
      ).
      Only one previous study by
      • Gross K.
      • Kircik L.
      • Kricorian G.
      5% 5-Fluorouracil cream for the treatment of small superficial basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction.
      investigated the effectiveness of topical fluorouracil twice daily for 6–12 weeks in 31 sBCCs (
      • Gross K.
      • Kircik L.
      • Kricorian G.
      5% 5-Fluorouracil cream for the treatment of small superficial basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction.
      ). The histological clearance rate at 3 weeks post-treatment was 90%. To our knowledge, no long-term follow-up studies have been reported.
      A previous systematic review and a network geometry review have shown that there is a lack of head-to-head comparison studies for treatment of sBCC (
      • Kim D.D.
      • Tang J.Y.
      • Ioannidis J.P.
      Network geometry shows evidence sequestration for medical vs. surgical practices: treatments for basal cell carcinoma.
      ,
      • Roozeboom M.H.
      • Arits A.H.
      • Nelemans P.J.
      • Kelleners-Smeets N.W.
      Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.
      ). Our study fulfills the need for a head-to-head comparison study by investigating the relative treatment effects between noninvasive therapies. Furthermore, a long-term follow-up study of fluorouracil in the treatment of sBCC is, to our knowledge, previously unreported. Currently, according to the European BCC guideline by Trakatelli et al., imiquimod and PDT are both considered good treatment options for low-risk sBCC (
      • Trakatelli M.
      • Morton C.
      • Nagore E.
      • Ulrich C.
      • Del Marmol V.
      • Peris K.
      • et al.
      Update of the European guidelines for basal cell carcinoma management.
      ). In addition, surgical excision (effectiveness of 89–98%) is considered reasonable but not essential (
      • Bath-Hextall F.
      • Ozolins M.
      • Armstrong S.J.
      • Colver G.B.
      • Perkins W.
      • Miller P.S.
      • et al.
      Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial.
      ,
      • Szeimies R.M.
      • Ibbotson S.
      • Murrell D.F.
      • Rubel D.
      • Frambach Y.
      • de Berker D.
      • et al.
      A clinical study comparing methyl aminolevulinate photodynamic therapy and surgery in small superficial basal cell carcinoma (8-20 mm), with a 12-month follow-up.
      ,
      • Trakatelli M.
      • Morton C.
      • Nagore E.
      • Ulrich C.
      • Del Marmol V.
      • Peris K.
      • et al.
      Update of the European guidelines for basal cell carcinoma management.
      ). Based on our findings, both imiquimod and fluorouracil are effective noninvasive treatments in most primary, low-risk sBCCs. When choosing a treatment for an individual patient with an sBCC, other factors such as age, compliance, and patient preferences should always be taken into account.
      To optimize treatment success, it is of great value to select the most effective treatment for an individual patient with an sBCC. We previously reported subgroup analyses showing that imiquimod is more effective than MAL-PDT in most sBCCs, with the exception of sBCCs localized on the lower extremities in older patients (
      • Roozeboom M.H.
      • Nelemans P.J.
      • Mosterd K.
      • Steijlen P.M.
      • Arits A.H.
      • Kelleners-Smeets N.W.
      Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial.
      ). At 3 years of follow-up, our conclusions remain unaltered: MAL-PDT may be preferable in elderly patients with sBCC on the lower extremities. MAL-PDT may also be an alternative therapy in a small group of patients for whom cream application is not feasible for practical reasons.
      The data provide no definite evidence for the superiority of imiquimod over topical fluorouracil. Both creams have an equal cosmetic outcome and risk of local adverse events (
      • Arits A.H.
      • Mosterd K.
      • Essers B.A.
      • Spoorenberg E.
      • Sommer A.
      • De Rooij M.J.
      • et al.
      Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
      ). Fluorouracil has the advantage of lower costs compared with imiquimod. In The Netherlands, the cost for a tube fluorouracil (40 g) is €29.19 and for imiquimod (36 sachets) €170.87 (

      Medicijnkosten. www.medicijnkosten.nl; 2016 (accessed 9 July 2015).

      ). At 12 months follow-up, both creams were cost effective compared with MAL-PDT, although the cost savings were larger for fluorouracil compared with imiquimod (
      • Arits A.H.
      • Spoorenberg E.
      • Mosterd K.
      • Nelemans P.
      • Kelleners-Smeets N.W.
      • Essers B.A.
      Cost-effectiveness of topical imiquimod and fluorouracil vs. photodynamic therapy for treatment of superficial basal-cell carcinoma.
      ). However, at 3 years of follow-up, the additional cost savings of fluorouracil compared with imiquimod may decrease, because the higher number of treatment failures requires an increase in surgical excisions. Perhaps even more important is the fact that between 1 and 3 years of follow-up, more recurrences were diagnosed in the fluorouracil group compared with the imiquimod group. This higher number of recurrences may necessitate a longer follow-up period for patients who are treated with fluorouracil. Consequently, the additional cost savings of fluorouracil compared with imiquimod will, in all probability, decrease substantially, because the costs of a yearly outpatient visit per patient have to be taken into account. More evidence on cost effectiveness is required to conclude whether imiquimod is more cost effective than fluorouracil.
      One limitation to a randomized controlled trial is that only patients who are willing to participate in a trial, and who have no specific treatment preference, can be randomized. In daily practice, not all patients can be motivated or are able to apply a cream daily for 6 weeks. For those patients, hospital-based treatments such as surgical excision, curettage and electrodessication, or PDT might be preferable. An additional limitation is that post-treatment biopsies were not performed to confirm lack of tumor in this study. The study was designed to make long-term clinical follow-up possible, in accordance with daily clinical practice, and large biopsies would have interfered with clinical follow-up. However, it is possible that clinical examination missed some subtle recurrences that will manifest after the end of the study. Furthermore, because patient preferences are very important in choosing an individual treatment, another limitation is that we have not evaluated the patient-reported outcomes on preference 3 years post-treatment.
      In summary, our study has shown that imiquimod is superior and fluorouracil not inferior to MAL-PDT in treatment of patients with sBCC. The data do not provide definite evidence for the superiority of imiquimod over fluorouracil. In terms of effectiveness, both creams are preferable to MAL-PDT treatment in most primary, low-risk sBCCs. However, to optimize treatment success, several other aspects regarding treatment choice should be taken into account for an individual patient with an sBCC.

      Materials and Methods

      Protocol

      This study compared long-term results between treatment with MAL-PDT and imiquimod or fluorouracil cream in patients with sBCC who participated in a noninferiority, randomized controlled trial that was conducted in seven hospitals in the southern part of The Netherlands (
      • Arits A.H.
      • Mosterd K.
      • Essers B.A.
      • Spoorenberg E.
      • Sommer A.
      • De Rooij M.J.
      • et al.
      Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
      ). Patients were recruited at the hospitals’ departments of dermatology between March 2008 and August 2010. Eligible patients had a histologically proven primary sBCC. Patients randomized to MAL-PDT (Metvix, Galderma SA, Penn Pharmaceutical Services, Gwent, UK) treatment were treated with one cycle of two treatments with a 1-week interval. Imiquimod treatment (Aldara, Meda AB, Solna, Sweden) required a period of 6 weeks during which patients applied the cream once daily (evening) for 5 consecutive days per week. Patient randomized to 5% fluorouracil cream (Efudix, Meda Pharmaceuticals, Amstelveen, The Netherlands) had to apply the cream twice daily (morning and evening) for a duration of 4 weeks. Additional treatment details have been described previously (
      • Arits A.H.
      • Mosterd K.
      • Essers B.A.
      • Spoorenberg E.
      • Sommer A.
      • De Rooij M.J.
      • et al.
      Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
      ). The primary study outcome was the probability that a patient was free of clinical evidence of tumor at all three follow-up visits, which is referred to as the 3-year probability of tumor-free survival. The need for retreatment after histological verification was considered as treatment failure. During follow-up, a physician blinded to treatment clinically assessed lesions for signs of treatment failure. Clinically observed treatment failures were histologically confirmed by a 3-mm punch biopsy. Relevant baseline patient and tumor characteristics were used for definition of subgroups. The full study design and procedures have been previously described (
      • Arits A.H.
      • Mosterd K.
      • Essers B.A.
      • Spoorenberg E.
      • Sommer A.
      • De Rooij M.J.
      • et al.
      Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
      ,
      • Roozeboom M.H.
      • Nelemans P.J.
      • Mosterd K.
      • Steijlen P.M.
      • Arits A.H.
      • Kelleners-Smeets N.W.
      Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial.
      ).
      The local medical ethics and scientific committee of the Maastricht University Medical Centre approved the protocol, and the study was performed in accordance with the Declaration of Helsinki. All participants provided written informed consent. The trial was registered as International Standard Randomized Controlled Trial (ISRCTN 79701845, 30/04/2008).

      Assignment and masking

      Participants were randomly assigned to receive MAL-PDT, imiquimod, or fluorouracil in a 1:1:1 ratio. Randomization was stratified by age (≤60 years vs. >60 years) and tumor location (head/neck vs. other). The research physician who assessed the treated lesions for signs of treatment failure was blinded to the assigned treatment modality and was not involved in the treatment. Patients and treating physicians were not masked for the assigned therapy. Statistical analysis was performed by two investigators not blinded to allocation.

      Participant flow and follow-up

      Patients who were tumor-free after 1 year of follow-up were invited for a follow-up visit to enable evaluation of a 3-year probability of tumor-free survival. For logistical reasons, follow-up visits were planned within a window of 3 months before or 3 months after the actual 3-year follow-up date.

      Statistical analysis

      Recorded baseline patient and tumor characteristics were summarized per treatment with descriptive statistics. The original sample size was estimated at 197 patients per treatment group. This sample size enabled detection of an absolute difference in 1-year recurrence-free survival of 10% (noninferiority margin) with a power of 80% and one-sided type I error of 5%. It was assumed that the proportion of patients with no tumor recurrence at 1 year after treatment with MAL-PDT would be 80% (
      • Braathen L.R.
      • Szeimies R.M.
      • Basset-Seguin N.
      • Bissonnette R.
      • Foley P.
      • Pariser D.
      • et al.
      Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology.
      ,
      • Telfer N.R.
      • Colver G.B.
      • Morton C.A.
      Guidelines for the management of basal cell carcinoma.
      ).
      Time-to-event analyses were performed to account for differences in follow-up between patients. Data were censored at diagnosis of a treatment failure or when loss to follow-up occurred. Both intention-to-treat and per-protocol analyses were performed. The cumulative probability of recurrence-free survival at 3 years post-treatment was estimated using Kaplan-Meier survival analysis. Cox proportional hazards models were used to calculate HRs for treatment failure with 95% CIs. To facilitate interpretation of HRs, the noninferiority margin of 10% for absolute differences in survival probability was translated to a noninferiority threshold on the relative risk scale based on the observed 3-year tumor-free survival probability (p0) in the MAL-PDT group:
      (log1–p0)/logp0
      (1)


      (
      • Com-Nougue C.
      • Rodary C.
      • Patte C.
      How to establish equivalence when data are censored: a randomized trial of treatments for B non-Hodgkin lymphoma.
      ). Reported P-values are two-tailed, corresponding with a one-sided significance level of 2.5% for testing noninferiority.
      Subgroup analyses were performed for subgroups defined by patient and tumor characteristics such as sex, age, tumor location, and tumor size. Additionally, Cox regression models including terms for characteristic by therapy interaction were used to test for statistical significance. Therapy was coded by two dummy variables. All data were analyzed using SPSS version 22.0 (SPSS, Chicago, IL) and STATA version 11.0 (STATA Corp., College Station, TX).

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      We thank the patients who agreed to participate in this study. We thank Han van Pelt, Carleine Thissen, Joris Rijzewijk, and Adrienne van Geest for contributing to this study. We thank all nurse practitioners, nursing staff, and employees of the secretarial department of the participating hospitals. We thank Nicole Luckerhof for her excellent administrative support. The study was financed by an unrestricted grant from The Netherlands Organization for Scientific Research ZonMw (08-82310-98-08626). ZonMw is a governmental institution financing research to improve health care in The Netherlands.
      This study is registered with the International Standard Randomized Controlled Trial (ISRCTN) registry, number 79701845. Date of assigned trial registration: 30 April 2008.
      The full protocol is available upon request.

      Disclaimer

      The funding source had no role in the design or conduct of the study collection, management, analysis, or interpretation of data or in the preparation, review, or approval of the manuscript.

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      Linked Article

      • Research that Guides Clinical Decisions
        Journal of Investigative DermatologyVol. 136Issue 8
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          The centerpiece of evidence-based medicine is the randomized controlled trial, a rigorous experiment. We use the study by Roozeboom et al. to illustrate how research guides clinical decisions. We describe levels of evidence, review criteria for assessing a trial regarding noninferiority of a therapy, and discuss challenges for evidence-based medicine in guiding care precisely targeted to an individual patient.
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