Klara Mosterd

Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial

BACKGROUND Superficial basal-cell carcinoma is most commonly treated with topical non-surgical treatments, such as photodynamic therapy or topical creams. Photodynamic therapy is considered the preferable treatment, although this has not been previously tested in a randomised control trial. We assessed the effectiveness of photodynamic therapy compared with imiquimod or fluorouracil in patients with superficial basal-cell carcinoma. METHODS In this single blind, non-inferiority, randomised controlled multicentre trial, we enrolled patients with a histologically proven superficial basal-cell carcinoma at seven hospitals in the Netherlands. Patients were randomly assigned to receive treatment with methylaminolevulinate photodynamic therapy (MAL-PDT; two sessions with an interval of 1 week), imiquimod cream (once daily, five times a week for 6 weeks), or fluorouracil cream (twice daily for 4 weeks). Follow-up was at 3 and 12 months post-treatment. Data were collected by one observer who was blinded to the assigned treatment. The primary outcome was the proportion of patients free of tumour at both 3 and 12 month follow up. A pre-specified non-inferiority margin of 10% was used and modified intention-to-treat analyses were done. This trial is registered as an International Standard Randomised controlled trial (ISRCTN 79701845). FINDINGS 601 patients were randomised: 202 to receive MAL-PDT, 198 to receive imiquimod, and 201 to receive fluorouracil. A year after treatment, 52 of 196 patients treated with MAL-PDT, 31 of 189 treated with imiquimod, and 39 of 198 treated with fluorouracil had tumour residue or recurrence. The proportion of patients tumour-free at both 3 and 12 month follow-up was 72.8% (95% CI 66.8-79.4) for MAL-PDT, 83.4% (78.2-88.9) for imiquimod cream, and 80.1% (74.7-85.9) for fluorouracil cream. The difference between imiquimod and MAL-PDT was 10.6% (95% CI 1.5-19.5; p=0.021) and 7.3% (-1.9 to 16.5; p=0.120) between fluorouracil and MAL-PDT, and between fluorouracil and imiquimod was -3.3% (-11.6 to 5.0; p=0.435. For patients treated with MAL-PDT, moderate to severe pain and burning sensation were reported most often during the actual MAL-PDT session. For other local adverse reactions, local skin redness was most often reported as moderate or severe in all treatment groups. 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. In the MAL-PDT group no serious adverse events were reported. One patient treated with imiquimod and two patients treated with fluorouracil developed a local wound infection and needed additional treatment in the outpatient setting. INTERPRETATION 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. FUNDING Grant of the Netherlands Organization for Scientific Research ZONMW (08-82310-98-08626).

Fractionated 5-aminolaevulinic acid-photodynamic therapy vs. surgical excision in the treatment of nodular basal cell carcinoma: Results of a randomized controlled trial

Background  Skin cancer incidence rates have been increasing for decades and this increase is expected to continue. Surgical excision (SE) is the treatment of first choice for nodular basal cell carcinoma (nBCC). Photodynamic therapy (PDT) has proven to be an effective treatment for superficial basal cell carcinoma. Its long‐term efficacy in nBCC has not yet been established.

Fractionated 5-aminolevulinic acid photodynamic therapy after partial debulking versus surgical excision for nodular basal cell carcinoma: A randomized controlled trial with at least 5-year follow-up

BACKGROUND Although effective in superficial basal cell carcinoma (BCC), the treatment effect of photodynamic therapy (PDT) in nodular BCC (nBCC) is still questionable. The relation between tumor thickness and PDT failure is unclear. OBJECTIVE We sought to compare long-term effectiveness of fractionated 20% 5-aminolevulinic acid (ALA)-PDT with prior partial debulking versus surgical excision in nBCC. The effect of tumor thickness on ALA-PDT failure was analyzed. METHODS 173 primary, histologically proven nBCCs in 151 patients were randomized to fractionated ALA-PDT (n = 85) or surgical excision (n = 88). Two PDT illuminations were performed with a 1-hour interval. Follow-up was at least 5 years posttreatment. Clinical recurrences were confirmed histologically. RESULTS A total of 171 nBCCs were treated and had a median follow-up of 67 months (range 0-106). At 60 months, 23 tumors had recurred in the ALA-PDT group and 2 tumors in the surgical excision group. Cumulative recurrence probabilities 5 years posttreatment were 30.7% (95% confidence interval [CI] 21.5%-42.6%) for ALA-PDT and 2.3% (95% CI 0.6%-8.8%) for surgical excision (P < .0001). Two tumors in the ALA-PDT group recurred at 72 and 91 months posttreatment. Cumulative probability of recurrence-free survival post-PDT was 65.0% (95% CI 51%-76%) for nBCC measuring greater than 0.7 mm in thickness and 94.4% (95% CI 67%-99%, P = .018) for tumors less than or equal to 0.7 mm. LIMITATIONS Tumor thickness on punch biopsy specimen might differ from the total lesion thickness. CONCLUSIONS In nBCC, 5-year cumulative probability of recurrence after surgical excision is lower than after fractionated ALA-PDT with prior debulking. Although surgical excision remains the gold standard of treatment, PDT might be an alternative for inoperable patients with thin (≤0.7 mm) nBCC.

Correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent basal cell carcinoma

BACKGROUND The type of treatment for a basal cell carcinoma (BCC) depends on the histologic subtype. Histologic examination is usually performed on incisional biopsy specimens. In primary BCC, the histologic subtype is correctly identified with a punch biopsy in 80.7% of cases. In recurrent BCC, correct identification is more difficult because of discontinuous growth caused by scar formation. Because an aggressive histologic subtype has a significantly higher risk for recurrence in these tumors, the histologic subtype is at least as important in recurrent BCC as it is in primary BCC. OBJECTIVE To investigate the correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent BCC. Furthermore, we sought to clarify how often an aggressive histologic subtype was missed, based on the punch biopsy specimen. METHODS We compared the histologic subtype in a punch biopsy specimen with the subsequent excision specimen in recurrent BCC. All BCCs were coded and judged randomly by the same dermatopathologist. RESULTS In 24 of 73 investigated BCCs (32.9%), the histologic subtype of the initial biopsy did not match with the histologic subtype of the subsequent excision. Of the 37 excised BCCs with an aggressive histologic subtype, 7 (19%) were missed by the initial punch biopsy. LIMITATIONS Intraobserver variation may have affected the results of this study. CONCLUSIONS Discriminating tumors with any aggressive growth is relevant for treatment. However, in recurrent BCC, the histology of the biopsy specimen does not always correlate with the histology of the definitive excision. This may have important therapeutic implications.

Histology-based Treatment of Basal Cell Carcinoma

Basal cell carcinoma is the most common type of skin cancer and its incidence is still rising. In recent years, new treatment modalities have been developed and existing modalities refined. The aim of this article is to give a histology-based overview of the available evidence-based research. The literature was searched for randomized controlled trials from which the efficacy of investigated treatments was obtained. Where possible, treatment modalities were evaluated specifically. Selection criteria were histological subtype, primary or recurrent basal cell carcinoma and tumour localization. Although surgery remains the preferred treatment for most basal cell carcinomas, patient and tumour characteristics should be taken into account when choosing the most suitable treatment.

Agreement between histological subtype on punch biopsy and surgical excision in primary basal cell carcinoma

Background  Diagnosis of clinically suspected basal cell carcinoma (BCC) by histological confirmation with punch biopsy has been recommended before treatment. Even shave biopsy has been proposed as useful to predict the correct subtype in primary BCC in 76–81%, whereas the agreement between histological BCC subtype on punch biopsy and subsequent excision specimens in recurrent BCC is 67.1%. However, no large studies on the agreement between histological BCC subtype seen on punch biopsy and the following surgical excision are performed in primary BCC.

Photodynamic therapy vs. topical imiquimod for treatment of superficial basal cell carcinoma: a subgroup analysis within a noninferiority randomized controlled trial

A recent noninferiority randomized controlled trial (RCT) indicated that imiquimod can be considered as superior to methylaminolevulinate photodynamic therapy (MAL‐PDT) in the treatment of superficial basal cell carcinoma (sBCC). Knowledge of treatment effectiveness in subgroups of patients is of great value in clinical practice to select the most effective treatment for an individual patient with sBCC.

Cost-effectiveness of topical imiquimod and fluorouracil vs. photodynamic therapy for treatment of superficial basal-cell carcinoma

A recent noninferiority randomized trial showed that in terms of clinical effectiveness imiquimod was superior and topical fluorouracil noninferior to methylaminolaevulinate photodynamic therapy (MAL‐PDT) for treatment of superficial basal‐cell carcinoma (sBCC). Although it was expected that MAL‐PDT would be more costly than either cream, a full cost‐effectiveness analysis is necessary to determine the balance between effectiveness and costs.

Photodynamic Therapy in Bowen's Disease: Influence of Histological Features and Clinical Characteristics on Its Success

Background: In Bowens disease (BD) there is no consensus on optimal treatment. Photodynamic therapy (PDT) is an effective non-invasive treatment modality for BD with excellent cosmetic results. Objective: This retrospective study examines whether clinical and histological features of BD impact PDT response. Methods: Patients with previously untreated BD from 2002 until 2007 were identified at the Maastricht University Medical Centre. Patients treated with PDT were included. All histological slides were re-examined. Results: During the study period 98 tumours were treated with PDT. In univariate analysis severe atypia and higher age were associated with decreased probability of clinical clearance. Higher age was also associated with an increased risk of recurrence. In multivariate analysis severe atypia remained the only independent risk factor for therapy failure. Conclusion: In patients with BD, severe atypia and higher age are associated with an increased risk of treatment failure after PDT.

Two-fold illumination in topical 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) for superficial basal cell carcinoma (sBCC): A retrospective case series and cohort study

BACKGROUND There is limited literature on efficacy using a 2-fold illumination scheme in aminolevulinic acid (ALA) photodynamic therapy for superficial basal cell carcinoma (sBCC). OBJECTIVES We sought to determine the efficacy of ALA photodynamic therapy for sBCC using a 2-fold illumination scheme after a single ALA application. Treatment failure within 12 months posttreatment was assessed. METHODS In this retrospective case series and cohort study, electronic files from patients treated between January 2010 and August 2011 were reviewed. Follow-up data were gathered until March 2014. RESULTS A total of 323 sBCC were analyzed for recurrence. Cumulative probability of clinical recurrence-free survival was 88.8% (95% confidence interval [CI] 85.4-92.4), 81.8% (95% CI 77.3-86.3), and 77.1% (95% CI 71.0-83.6) at 12, 24, and 48 months, respectively. For histologically confirmed recurrences this was 90.2% (95% CI 86.9-93.5), 85.4% (95% CI 75.5-89.3), and 81.8% (95% CI 75.5-88.1), respectively. A worse recurrence-free survival for tumors in the head and neck area and tumors larger than 10 mm was observed. LIMITATIONS The retrospective nature and the lack of a control group are limitations. CONCLUSIONS ALA photodynamic therapy using a 2-fold illumination scheme might be a feasible treatment option with acceptable long-term results for small sBCC located outside the head and neck area.