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Five-Year Results of a Randomized Controlled Trial Comparing Effectiveness of Photodynamic Therapy, Topical Imiquimod, and Topical 5-Fluorouracil in Patients with Superficial Basal Cell Carcinoma
Correspondence: Maud H.E. Jansen, Department of Dermatology, Maastricht University Medical Centre, P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
Department of Dermatology, Maastricht University Medical Centre, Maastricht, The NetherlandsGROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
Department of Dermatology, Maastricht University Medical Centre, Maastricht, The NetherlandsGROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
Department of Dermatology, Maastricht University Medical Centre, Maastricht, The NetherlandsGROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The NetherlandsDepartment of Dermatology, Catharina Hospital, Eindhoven, The Netherlands
Department of Dermatology, Maastricht University Medical Centre, Maastricht, The NetherlandsGROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
Department of Dermatology, Maastricht University Medical Centre, Maastricht, The NetherlandsGROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The NetherlandsDepartment of Dermatology, Catharina Hospital, Eindhoven, The Netherlands
Department of Dermatology, Maastricht University Medical Centre, Maastricht, The NetherlandsGROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
For the treatment of superficial basal cell carcinoma, a prospective, noninferiority, randomized controlled multicenter trial with 601 patients showed that 5% imiquimod cream was superior and 5-fluorouracil cream not inferior to methyl aminolevulinate photodynamic therapy (MAL-PDT) at 1 and 3 years after treatment. No definite conclusion could be drawn regarding the superiority of imiquimod over 5-fluorouracil. We now present the 5-year follow-up results according to the intention-to-treat analysis. Five years after treatment, the probability of tumor-free survival was 62.7% for methyl aminolevulinate photodynamic therapy (95% confidence interval [CI] = 55.3–69.2), 80.5% for imiquimod (95% CI = 74.0–85.6), and 70.0% for 5-fluorouracil (95% CI = 62.9–76.0). The hazard ratio for treatment failure of imiquimod and 5-fluorouracil were 0.48 (95% CI = 0.32–0.71, P < 0.001) and 0.74 (95% CI = 0.53–1.05, P = 0.09), respectively, when compared with methyl aminolevulinate photodynamic therapy. Compared with 5-fluorouracil, imiquimod showed a hazard ratio of 0.65 (95% CI 0.43–0.98, P = 0.04). In conclusion, 5 years after treatment, the results of this trial show that 5% imiquimod cream is superior to both methyl aminolevulinate photodynamic therapy and 5-fluorouracil cream in terms of efficacy for superficial basal cell carcinoma. We therefore consider 5% imiquimod cream as the first choice for noninvasive treatment in most primary superficial basal cell carcinomas.
Basal cell carcinoma (BCC), the most common nonmelanoma skin cancer among the white population, is an important health problem worldwide and has a rapidly increasing incidence (
). Although surgical excision is the gold standard for treatment of BCCs, different studies suggest that noninvasive therapies are useful alternatives to surgery for treatment of superficial BCC (sBCC) (
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.
Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial.
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.
Only a few studies on long-term effectiveness of noninvasive treatment of sBCC have been published. Head-to-head studies are pivotal to reach consensus in international BCC guidelines on the first choice noninvasive treatment to compare effectiveness (
Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.
). We previously showed that the efficacy of 5% imiquimod cream is superior and 5-fluorouracil cream not inferior to methyl aminolevulinate photodynamic therapy (MAL-PDT) in the treatment of sBCC at 3-year follow-up (
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.
). The aim of this study is to report the comparative efficacy of MAL-PDT, imiquimod, and 5-fluorouracil 5 years after treatment.
Results
Patients
A total of 601 patients with a primary, histologically proven sBCC were randomly assigned to treatment with MAL-PDT (n = 202), imiquimod (n = 198), or 5-fluorouracil (n = 201). Baseline characteristics are presented in Table 1. Additional information on these characteristics can be found in a previous report (
Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
). Patient flow from recruitment to the 5-year follow-up visit is shown in Figure 1. All participating patients were invited for a follow-up visit at 5 years after the end of treatment. Five patients (two from the MAL-PDT group and three imiquimod group) who were previously considered lost to follow-up, because they were previously unable or unwilling to attend their follow-up visits, were willing to participate at the 5-year follow-up visit. In five patients, protocol deviations occurred because of strong clinical suspicion of recurrence: surgical excision in three patients and noninvasive treatment in two patients. Because these patients could not be assessed for recurrence during the primary noninvasive treatment during follow-up, they were considered lost to follow-up. A total of 87 patients (14.9%) were lost to follow-up, of whom 32 were treated with MAL-PDT, 31 with imiquimod, and 24 with 5-fluorouracil. Reasons for not completing follow-up were death due to causes unrelated to sBCC or treatment, refusal to attend follow-up visits, and other reasons such as inability of the patient to visit the hospital. The median follow-up period in the study was 64 months (range = 1–93).
Table 1Distribution of patient and tumor characteristics
From randomization until 5 years after treatment, 70 tumor recurrences were found in the MAL-PDT group, 36 in the imiquimod group, and 57 in the 5-fluorouracil group. Thirteen of the 70 recurrences occurred between 3 and 5 years of follow-up (four after MAL-PDT, two after imiquimod, and seven after 5-fluorouracil treatment) (Figures 1 and 2).
Estimates of the cumulative probability of tumor-free survival, according to the intention-to-treat and per protocol analysis, at 1, 3 and 5 years after treatment are presented in Table 2. At 5 years after treatment, the probability of tumor-free survival is 62.7% for MAL-PDT (95% confidence interval [CI] = 55.3–69.2), 80.5% for imiquimod (95% CI = 74.0–85.6), and 70.0% for 5-fluorouracil (95% CI = 62.9–76.0). Based on the estimated 5-year tumor-free survival probability of 62.7% for MAL-PDT, the noninferiority margin of 10% for absolute differences in survival probability translates to a noninferiority threshold for the hazard ratio (HR) for treatment failure of 1.37 (log 0.527/log 0.627) (
). Consequently, noninferiority of both creams to MAL-PDT can be concluded if the 95% CIs of the corresponding HRs are entirely below 1.37. Superiority of both creams to MAL-PDT can be concluded if the 95% CIs of the corresponding HRs are entirely below 1.0.
Table 2Cumulative probability of tumor-free survival 1, 3, and 5 years after treatment with MAL-PDT, imiquimod, or 5-fluorouracil for sBCC
Time after Treatment
MAL-PDT
Imiquimod
5-Fluorouracil
ITT, % (95% CI)
PP, % (95% CI)
ITT, % (95% CI)
PP, % (95% CI)
ITT, % (95% CI)
PP, % (95% CI)
1 year
73.0 (66.1–78.7)
73.4 (66.6–79.0)
83.5 (77.4–88.1)
83.5 (77.4–88.1)
80.1 (73.8–85.0)
79.8 (73.4–84.8)
3 year
65.3 (58.0–71.6)
65.3 (58.1–71.5)
81.8 (75.5–86.7)
81.8 (75.5–86.7)
74.2 (67.4–79.8)
74.4 (67.5–80.0)
5 year
62.7 (55.3–69.2)
62.7 (55.4–69.2)
80.5 (74.0–85.6)
80.5 (74.0–85.6)
70.0 (62.9–76.0)
70.1 (62.9–76.1)
Abbreviations: CI, confidence interval; ITT, intention to treat; MAL-PDT, methyl aminolevulinate photodynamic therapy; PP, per protocol; sBCC, superficial basal call carcinoma.
The HR for treatment failure comparing imiquimod with MAL-PDT was 0.48 (95% CI = 0.32–0.71, P < 0.001) (Table 3). The data also allow comparison of imiquimod with 5-fluorouracil. The HR of 0.65 (95% CI = 0.43–0.98, P = 0.04) shows that imiquimod is also superior to 5-fluorouracil. Comparison of 5-fluorouracil with MAL-PDT resulted in an HR of 0.74 (95% CI = 0.53–1.05, P = 0.09). According to the intention-to-treat analysis, after 5 years of follow-up, imiquimod was superior compared with MAL-PDT and 5-fluorouracil. 5-fluorouracil is not inferior to MAL-PDT. Almost identical results were found in the per protocol analysis (Tables 2 and 3). A sensitivity analysis, wherein the tumors of the five patients with protocol deviations were considered as recurrences instead of lost-to-follow-up, indicated robustness of the results (see Supplementary Tables S1 and S2 online).
Table 3Absolute differences and HRs with 95% CI of tumor-free survival at 5-year follow-up
Based on the 5-year probabilities of remaining free from recurrence, one recurrence can be prevented for every 5.6 patients (95% CI = 3.7–11.4) treated with imiquimod instead of MAL-PDT and for every 9.5 patients (95% CI = 5.2–57.4) treated with imiquimod instead of 5-fluorouracil.
Discussion
The results of our study showed that treatment with 5% imiquimod cream is superior to both MAL-PDT and 5-fluorouracil in treatment of sBCC, 5 years after treatment, in terms of efficacy. To our knowledge, this is the first prospective head-to-head comparison study on three different noninvasive therapies in the treatment of sBCC with a follow-up of 5 years. We confirmed superiority of 5% imiquimod cream over MAL-PDT and also found evidence for superiority of imiquimod over 5-fluorouracil cream, which had not yet manifested itself at 1 and 3 years of follow-up (
Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
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.
Our finding that imiquimod has a tumor-free survival of 80.5% after 5 years of follow-up is comparable with findings of other studies. A recent randomized controlled trial by
, which compared surgical excision with topical imiquimod cream in 501 patients with sBCC, reported a 5-year success rate of 83.8%. Only one recurrence was found between 3 and 5 years of follow-up after treatment with imiquimod, which is comparable to the low number of recurrences (n = 2) found in our study in the same follow-up interval. Two other studies on imiquimod treatment for sBCC reported 5-year success rates of 80.4% (95% CI = 74.4–86.4%) and 77.9% (
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.
The results of this study showed that MAL-PDT has a probability of tumor-free survival of 62.7% at 5 years after treatment. Only one other study on MAL-PDT with a 5-year follow-up period is available for comparison (
). This study included 114 sBCCs in 60 patients and showed a 5-year success rate of 75% (95% CI = 64.3–83.3%). This discrepancy may be explained by the fact that the latter study retreated patients with initial incomplete response and excluded patients that had a treatment failure at 3 months. This introduces bias toward a more favorable long-term result of PDT. To the best of our knowledge, no studies with long-term follow-up results after treatment with 5-fluorouracil for sBCC have been published. The efficacy of 5-fluorouracil in the treatment of sBCC was evaluated in one study (
5% 5-Fluorouracil cream for the treatment of small superficial Basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction.
). This study used a longer treatment regimen of 6 to 12 weeks and reported a cure rate of 90% at 3 weeks after treatment. A longer treatment period might positively influence the results of 5-fluorouracil.
In the European Guidelines, updated in 2014, all three studied noninvasive therapies are considered as an effective treatment for sBCC (
). Our data suggest that based on efficacy, 5% imiquimod cream should be the noninvasive treatment of first choice. PDT and 5-fluorouracil could be reserved for situations where there is a relative or absolute contraindication to using imiquimod. PDT may be more effective in specific subgroups of patients. We previously performed subgroup analyses indicating that in older patients with an sBCC on the lower extremities, MAL-PDT was significantly more effective than imiquimod. (
Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial.
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.
) Because our study was not designed for subgroup analyses, these findings need to be validated in another study.
Patient preferences should also be considered when choosing a therapy. A discrete choice experiment, which was performed alongside our study, showed that effectiveness of a therapy was the most important driver for treatment preference (
also showed that 124 patients with a BCC valued a high chance of cure the most, but when the BCC was located in the head or neck region and if the BCC was recurrent, patients were willing to trade risk of recurrence for better cosmetic results. Two other discrete choice experiments showed that patients preferred a better cosmetic result rather than a higher level of effectiveness. It must be noted that in these studies topical treatments (MAL-PDT or imiquimod cream) were compared with surgical excision (
What determines patient preferences for treating low risk basal cell carcinoma when comparing surgery vs imiquimod? A discrete choice experiment survey from the SINS trial.
Discrete choice to experiment to derive willingness to pay for methyl aminolevulinate photodynamic therapy versus simple excision surgery in basal cell carcinoma.
). Furthermore, adverse events should also be taken into account. As previously reported, all therapies showed local adverse events, such as pain or skin redness (
Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
). Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT. However, for all studied treatments, no major adverse events were reported (
Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
). From a cost perspective, 5-fluorouracil may be considered an attractive alternative, because costs of 5-fluorouracil are much lower than costs of imiquimod. In The Netherlands, the cost of a 40-g tube of 5-fluorouracil is €31.32, compared with €177.41 for 36 sachets of imiquimod 5% cream (
) However, because of the much higher risk of recurrences 5 years after treatment with 5-fluorouracil, we do not think that, from a clinical perspective, the potential higher cost savings can justify the lower efficacy. When choosing a treatment, the various treatment aspects should be taken into account to enable patients with an sBCC to make a well-informed decision.
A limitation of this study is the loss-to-follow-up of 87 out of 601 randomized patients (14.9%), which is a common problem in studies with long-term follow-up. For logistic reasons it was not possible to plan all control visits at exactly 1, 3, and 5 years after the end of treatment. Actual dates of follow-up visits could take place before or after the pre-planned dates. For this reason, the previously published 3-year results show some discrepancies with the 3-year results reported in this study (
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.
). In this study, patient observations were censored at exactly 36 months after treatment (the planned date), whereas in the previous report, the actual date of the 3-year follow-up visit was used for censoring when this date preceded the planned date. The absolute 3-year probabilities of tumor-free survival for all three noninvasive treatments were therefore slightly underestimated compared with the absolute probability estimates in this article. However, the estimates of the relative effectiveness of the three treatment modalities were not affected.
In conclusion, the results of this trial show that after 5 years of follow-up, 5% imiquimod is superior to both MAL-PDT and 5-fluorouracil in treatment of patients with primary sBCC. We therefore consider 5% imiquimod as the first choice noninvasive treatment in most primary sBCCs in terms of efficacy. However, there is a need for multiple experiments from disparate investigators showing a similar trend/outcome.
Materials and Methods
Protocol
Long-term results were evaluated with data from a single-blinded, noninferiority, multicenter study in which patients with sBCC were randomized between treatment with MAL-PDT, imiquimod, or 5-fluorouracil cream (
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 dermatology departments of seven hospitals in The Netherlands between March 2008 and August 2010. The extensive study design and procedures have been described elsewhere, but will be briefly described here (
Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
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.
Primary inclusion criteria for the 601 participants were patients with a primary sBCC that was histologically confirmed on a 3-mm punch skin biopsy. One tumor per patient was included. Excluded were patients using immunosuppressive drugs, suffering from genetic cutaneous cancer disorders, having tumors located in the high-risk area of the face (H-zone) or scalp, and women who were pregnant or breastfeeding.
Treatment with MAL-PDT (Metvix, Galderma SA, Penn Pharmaceutical Services, Gwent, UK) involved two single treatments with a 1-week interval (fluence = 630 nm, dose = 37 J/cm2). Patients randomized to receive 5% imiquimod cream (Aldara, Meda AB, Solna, Sweden) applied the cream once daily for 5 consecutive days a week for 6 weeks. Treatment with 5% 5-fluorouracil cream (Efudix, Meda Pharmaceuticals, Amstelveen, Netherlands) involved application of the cream twice daily for 4 weeks.
The primary study outcome in this study was defined as the cumulative probability of remaining free of tumor recurrence at 5 years after treatment, which is referred to as the 5-year probability of tumor-free survival. Treatment failure was defined as a histologically confirmed BCC on a skin biopsy sample from a clinically suspect area within 10 mm of the scar of the biopsy. Follow-up visits were planned at 3, 12, 36, and 60 months after end of treatment and were performed by an investigator who was blinded to treatment assignment.
The study was performed in accordance with the Declaration of Helsinki Principles, and approval of the local medical ethics and scientific committee of the Maastricht University Medical Centre was obtained. All participants provided written, informed consent before enrolment. The trial was registered as International Standard Randomized Controlled Trial (ISRCTN 79701845).
Assignment and masking
Participants were randomly assigned to one of the three treatments in a 1:1:1 ratio. Stratifying factors were age and tumor location (head/neck vs. other). Follow-up visits were performed by an investigator who was blinded to treatment assignment and was not involved in the treatment. Patients and treating physicians were not blinded to the allocated treatment.
Participant flow and follow-up
All participating patients were invited for a follow-up visit at 5 years after the end of treatment. For logistical reasons, follow-up visits were planned within a window of 6 months before or 6 months after the actual 5-year follow-up date.
Statistical analysis
Effectiveness
For descriptive purposes, categorical variables were presented as numbers and percentages, and mean (± standard deviation) or median with range were reported for continuous variables. The original sample size of 197 patients per randomized group was based on the statistical ability to detect an absolute difference of 10% in 1-year probability of tumor-free survival (noninferiority margin) between groups, with a power of 80% and one-sided alpha of 5%. The full rationale for the sample size calculation of this study has been described in earlier publications on this trial (
Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
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.
Time-to-event analyses were performed to account for differences in follow-up between patients. In case of recurrence of a treated lesion, patients were censored at the date of recurrence or at the date of last follow-up visit. Because of logistic reasons, the actual date of follow-up visits did not always coincide exactly with the planned dates (at 3, 12, 36, and 60 months after treatment). For the Kaplan-Meier analysis, we used the planned dates, assuming that the observed health state (treatment failure or not) reflected the health state at the moment that the visit should have taken place.
Cox proportional hazards models were used to calculate hazard ratios for treatment failure with 95% CIs. To facilitate interpretation of HRs, the noninferiority margin of 10% for absolute differences in tumor-free survival probability was translated into a noninferiority threshold on the relative risk scale based on the observed 5-year tumor-free survival probability (p0) in the MAL-PDT group (log[p0 – 0.1]/log[p0]) (
We thank the patients who agreed to participate in this study. We thank M. de Rooij, C. Thissen, J. Rijzewijk, and A. 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. We thank Kiki Frencken for her unrelenting commitment to and enthusiasm for this study.
The study was financed by a grant of 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. The funding source had no role in the design or conduct of the study collection; management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.
The trial is registered as an International Standard Randomized controlled trial (ISRCTN) 79701845. Date of clinical trial registration: 30 April 2008.
Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial.
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.
5% 5-Fluorouracil cream for the treatment of small superficial Basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction.
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.
Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.
Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial.
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.
What determines patient preferences for treating low risk basal cell carcinoma when comparing surgery vs imiquimod? A discrete choice experiment survey from the SINS trial.
Discrete choice to experiment to derive willingness to pay for methyl aminolevulinate photodynamic therapy versus simple excision surgery in basal cell carcinoma.
Superficial basal cell carcinoma is a type of keratinocyte carcinoma that has increasing incidence and substantial morbidity. Jansen et al. report on a randomized trial with 5 years of follow-up that found imiquimod to be more effective than 5-fluorouracil or methyl aminolevulinate photodynamic therapy in preventing superficial basal cell carcinoma recurrence. However, the toxicity and cost of topical treatments, as well as patient preferences, need to be evaluated when making treatment decisions in clinical practice.
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