Photodynamic Therapy Using Topical Methyl Aminolevulinate Vs Surgery for Nodular Basal Cell Carcinoma Results of a Multicenter Randomized Prospective Trial

STUDY Photodynamic Therapy Using Topical Methyl Aminolevulinate vs Surgery for Nodular Basal Cell Carcinoma Results of a Multicenter Randomized Prospective Trial

Lesley E. Rhodes, MD, FRCP; Menno de Rie, MD; Ylva Enstro¨m, MD; Richard Groves, FRCP; Tore Morken, MD; Victoria Goulden, MRCP; Gavin A. E. Wong, MRCP; Jean-Jacques Grob, MD; Sandeep Varma, MRCP; Peter Wolf, MD

Background: Photodynamic therapy (PDT) is increas- Cosmesis and lesion recurrence were further assessed at ingly used as a noninvasive treatment for nodular basal 24 months. cell carcinoma (BCC), without a sound evidence base. Results: Data from 97 patients (105 lesions) were in- Objective: To compare topical PDT, with the use of the cluded in the 3-month per-protocol analysis. Complete sensitizer methyl aminolevulinate, and standard exci- response rates did not differ significantly between groups sion surgery in nodular BCC. (51/52 [98%] lesions with surgery vs 48/53 [91%] lesions with methyl aminolevulinate PDT; difference [95% Design: Prospective, randomized study. confidence interval], 4.8% (−3.4% to 13.0%]; P=.25). At 12 months, tumor-free rates were 50 (96%) of 52 le- Setting: University dermatology departments. sions with surgery vs 44 (83%) of 53 with methyl aminolevulinate PDT (P=.15). More patients treated with Patients: A total of 101 adults with previously un- methyl aminolevulinate PDT than surgery had an excel- treated nodular BCC. lent or good cosmetic outcome at all time points (significant at 12 and 24 months on patient assessment, Interventions: Patients received methyl aminolevuli- PϽ.05, and at 3, 12, and 24 months on investigator evalu- nate PDT (n=52) or surgery (n=49). The PDT was given ation, PϽ.001). At 24 months, 5 lesions that had ini- twice, 7 days apart, with methyl aminolevulinate cream tially cleared with methyl aminolevulinate PDT had re- (160 mg/g) and 75 J/cm2 red light (570-670 nm). Thir- curred, compared with 1 after surgery. teen patients with a noncomplete response to PDT at 3 months (24% lesions) were retreated. Conclusions: Methyl aminolevulinate PDT is an effective treatment for nodular BCC, and while there is a trend Outcome Measures: Primary end point was clini- for higher recurrence with this modality, it conveys the cally assessed lesion clearance at 3 months after treat- advantage over surgery of better cosmesis. ment. Secondary end points were sustained response rate at 12 months and cosmetic outcome at 3 and 12 months. Arch Dermatol. 2004;140:17-23

KIN CANCER IS THE MOST sue invasion and destruction is signifi- common cancer in white cant. Simple surgical excision is regarded populations, with an esti- as the treatment of choice for BCCs of the mated incidence of 1100 per nodular type5,6; however, cosmetic out- 1 million population per year come may be less than optimal. in northwest Europe,1 and twice and 10 Photodynamic therapy (PDT) offers S 2 times this number in the United States and the advantages over surgery of being a noninvasive procedure causing minimal dam- See also pages 26, 33, age to surrounding tissue, because of relatively selective uptake of photosensitizer 41, and 116 by malignant cells. Activation by visible CME course available at light releases reactive oxygen species that www.archdermatol.com produce local tissue destruction.7 Topi- cal PDT has been increasingly practiced 3 Author affiliations are listed Australia, respectively. Moreover, the in- since the description of 5-aminolevulinic 4 at the end of this article. cidence continues to rise. Basal cell car- acid, a precursor in heme biosynthesis, as The authors have no relevant cinoma (BCC) is the most frequent form, prodrug.8 Application of excess 5-ami- financial interest in this article. and the morbidity associated with local tis- nolevulinic acid results in buildup of pho-

(REPRINTED) ARCH DERMATOL / VOL 140, JAN 2004 WWW.ARCHDERMATOL.COM 17

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 toactive porphyrins including protoporphyrin IX. Any ficient to cause pain or bleeding. A 1-mm-thick layer of methyl protoporphyrin IX formed, or remaining, after light ex- aminolevulinate cream was applied to each lesion and 5 mm posure is metabolized within 48 hours. Ease of applica- of surrounding tissue and covered with an adhesive occlusive tion of 5-aminolevulinic acid PDT has resulted in its wide- dressing (eg, Tegaderm; 3M Corp, St Paul, Minn) for 3 hours. spread use in several countries, without license, and in Dressings were then removed and the cream was washed off with 0.9% saline solution, immediately before illumination with the absence of randomized prospective trials with stan- 9 noncoherent red light from a standard light source (Cure- dard surgical treatment. Large series of BCCs treated with light; PhotoCure ASA), with emission spectrum of 570 to 670 5-aminolevulinic acid PDT show complete response rates nm, total fluence of 75 J/cm2, and fluence rate of 50 to 200 mW/ of 34% to 100%, with inferior clearance in nodular com- cm2. Fluence rate depended on distance of the lamp from the pared with superficial BCC.10 Routine double PDT treat- lesion, which was adjusted to achieve field sizes 3.5 to 5.5 cm ment may improve procedure efficacy.11 in diameter, as appropriate. Simple elliptical excision surgery Methyl aminolevulinate, the methyl ester of 5-ami- with at least 5-mm margins was performed with the patient un- nolevulinic acid, may offer advantages over 5-aminolevu- der local anesthesia in accordance with the usual practice of linic acid in terms of improved skin penetration be- the center. cause of enhanced lipophilicity12,13 and specificity for neoplastic cells.14 Initial experience suggests that methyl END POINT ASSESSMENTS aminolevulinate PDT is a promising treatment for BCC.15 At 3 months after the initial treatment, lesions were evaluated The aim of this first multicenter, randomized, parallel- by clinical inspection by the same investigator and rated as either group, prospective study was to compare the efficacy and complete response, ie, complete disappearance of the lesion, or cosmetic outcome of topical methyl aminolevulinate PDT noncomplete response, ie, noncomplete disappearance of the le- with standard simple excision surgery in primary nodu- sion. Lesions with noncomplete response to PDT at 3 months lar BCC. received a second treatment cycle and were reevaluated 3 months later. Further treatment of patients who did not show complete response to surgery at 3 months depended on the standard prac- METHODS tice of the center concerned. Investigator-assessed cosmetic outcome was evaluated 3 months after surgery or the last PDT treat- PATIENTS ment (ie, at 3 months for patients who required 1 PDT cycle and 6 months for patients who required 2 PDT cycles), in all pa- Between October 29, 1999, and September 8, 2000, 103 patients who had shown a complete response in all lesions, and tients were enrolled from the specialist dermatology clinics of on the basis of a 4-point scale: (1) excellent: no scarring, atro- participating centers. All subjects were 18 years or older and phy, or induration, slight or no redness or change in pigmenta- had previously untreated primary nodular BCC suitable for tion compared with adjacent skin; (2) good: no scarring, atro- simple excision surgery. Diagnosis of clinically apparent nodu- phy, or induration, moderate redness or increase in pigmentation lar BCC was confirmed histologically. Excluded from the study compared with adjacent skin; (3) fair: slight to moderate occur- were patients with more than 10 eligible lesions; lesions in the rence of scarring, atrophy, or induration; and (4) poor: exten- midface region, orbital areas, and ears; lesions with a longest sive occurrence of scarring, atrophy, or induration. Evaluation diameter of less than 6 mm or more than 15 mm (face or scalp), of cosmetic outcome was repeated at the 12-month and 24- more than 20 mm (extremities or neck), or more than 30 mm month follow-up visits. In addition, patients gave a global as- (trunk); and pigmented, or morpheaform BCCs. Patients with sessment of cosmetic outcome on a similar 4-point scale (rang- porphyria, Gorlin syndrome, or a history of arsenic exposure; ing from excellent to poor) at 3, 12, and 24 months. Clinical those who had participated in any other investigational study evaluation for detection of lesion disease involvement or recur- in the past 30 days; those likely to be poor compliers; those rence was performed at 12 and 24 months after treatment. taking immunosuppressive medication; and women who were pregnant or breastfeeding were excluded. The study was ap- ADVERSE EVENTS proved by the local ethics committee responsible for each center and conducted in accordance with the Declaration of Hel- Local skin reactions during and after cream application and il- sinki (South Africa, 1996). Patients gave written informed lumination were documented. Adverse events (ie, any unfa- consent before study entry. vorable and unintended sign, symptom, or disease) either reported spontaneously by the patient or elicited after nonleading STUDY DESIGN questioning were noted at each follow-up visit, together with their severity, duration, and need for additional therapy. The Within 4 weeks of the screening visit, eligible patients were ran- severity of the adverse event was rated as follows: mild, tran- domized consecutively to treatment with PDT with the use of sient and easily tolerated; moderate, caused the patient dis- methyl aminolevulinate cream, 160 mg/g (Metvix; PhotoCure comfort and interrupted usual activities; and severe, caused con- ASA, Oslo, Norway) or excision surgery. The randomization siderable interference with usual activities and may have been list was kept centrally, and investigators called or faxed to the incapacitating or life-threatening. Local phototoxicity reac- monitor when a new patient was included to find out the treat- tions were graded in accordance with the National Cancer In- ment allocated to that patient number. Randomization was strati- stitute Common Toxicity Criteria16 relevant to the skin. The fied by center and number of eligible lesions per patient (1-3 clinician assessed the causal relationship of the event to the study and Ն4). Patients randomized to PDT were treated with either treatment as related, uncertain, or not related. 1 or 2 PDT cycles, each comprising 2 PDT sessions, with an interval of 1 week between sessions. Before application of methyl STATISTICAL ANALYSIS aminolevulinate cream to the lesion, surface crust or scale was gently removed with a curette or scalpel blade. This superfi- The primary variable in the study was complete response based cial lesion preparation was performed in a standardized man- on investigator assessments of the lesions 3 months after the ner between centers, without anesthesia, such as to be insuf- last PDT treatment or surgical excision. Lesion response was

(REPRINTED) ARCH DERMATOL / VOL 140, JAN 2004 WWW.ARCHDERMATOL.COM 18

MAL-PDT, n = 53 (60) Surgery, n = 50 (58)

Not Treated, Consent Withdrawn, n = 1 (5) Not Treated, Consent Withdrawn, n = 1 (3)

ITT Population, n = 52 (55) ITT Population, n = 49 (55)

Protocol Deviation, n = 1 (1) Discontinuation, n = 2 (3) 1 (2) Consent Withdrawn 1 (1) Death Discontinuation, Adverse Event, n = 1 (1)

PP Population, n = 50 (53) PP Population, n = 47 (52)

Noncomplete Response, n = 5 (5) Noncomplete Response, n = 1 (1)

Discontinuation, n = 2 (2) Discontinuation (Death), n = 1 (1) 1 (1) Withdrawn Consent 1 (1) Adverse Event (Death)

12-mo Follow-up, n = 43 (46) 12-mo Follow-up, n = 45 (50)

Recurrent at 12 mo, n = 2 (2) Recurrent at 12 mo, n = 0

Missing at 24-mo Follow-up, n = 4 (6) Missing at 24-mo Follow-up, n = 2 (3)

Discontinuation, n = 3 (3) Discontinuation (Death), n = 2 (2) 2 (2) Deaths 1 (1) Withdrawn Consent

24-mo Follow-up, n = 34 (35) 24-mo Follow-up, n = 41 (45)

Recurrent at 24 mo, n = 3 (3) Recurrent at 24 mo, n = 1 (1)

24-mo Known Sustained Response, 24-mo Known Sustained Response, n = 31 (32) n = 40 (44)

Figure 1. Patient disposition. Numbers of lesions are given in parentheses. MAL-PDT indicates methyl aminolevulinate photodynamic therapy; ITT, intent-to-treat; and PP, per-protocol.

regarded as independent between lesions, even within the same RESULTS patient. Assuming that an estimated 95% of lesions would show complete response to simple excision surgery, and that the response to PDT would be the same in this study population, it PATIENTS was estimated that approximately 50 lesions per treatment group would be required to demonstrate with 95% confidence and a A total of 101 of 103 randomized patients received the power of 90% that methyl aminolevulinate PDT was no more study treatment; 52 patients were treated with methyl ami- than 15% inferior to simple excision therapy. The 15% differ- nolevulinate PDT and 49 patients were treated with simple ence was agreed on before study commencement as being clini- excision surgery. Two patients, 1 patient in each treat- cally relevant by the dermatologists who participated in the study. ment group, withdrew consent before receiving treat- Per-protocol analysis of pooled data including all eligible patients who completed surgery or the first PDT cycle and had at ment and were therefore excluded from the study least 1 response assessment at 3 months, or who completed a (Figure 1). The baseline characteristics of the 2 treat- second PDT cycle and received treatment in accordance with ment groups were similar (Table 1). The majority of the protocol procedures, was performed independently by patients in each group had 1 lesion (49/52 [94%] in the Parexel GmbH, Berlin, Germany, using SAS software (SAS In- methyl aminolevulinate PDT group and 43/49 [88%] in stitute Inc, Cary, NC). Two-sided 95% confidence intervals for the surgery group); most lesions were less than 15 mm the complete response rate were calculated for the difference in diameter and were located on the face and scalp or the between treatment groups. If the upper limit of this interval trunk and neck (Table 1). Most lesions in the methyl ami- was less than 15%, it was concluded that methyl aminolevuli- nolevulinate PDT group were treated with 1 PDT cycle nate PDT was not inferior to surgery. Since this was a multi- (42/55 [76%]). Patients received a light dose of 75 J/cm2, center study involving 13 centers, a Mantel-Haenszel analysis at mean light intensity of 127 mW/cm2 (range, 50-200 was also performed to account for center differences in com- 2 plete response. The numbers of patients with excellent or good mW/cm ). overall cosmetic outcome were compared between the treat- Four patients, 2 in the methyl aminolevulinate PDT ment groups. Sustained tumor-free response rates at 12 months group and 2 in the surgery group, were excluded from per- were reported for each treatment group. protocol analysis of the 3-month efficacy data. In the methyl

(REPRINTED) ARCH DERMATOL / VOL 140, JAN 2004 WWW.ARCHDERMATOL.COM 19

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 sponse rate at 12 months included evaluation of both Table 1. Baseline Characteristics, All Treated Patients nonresponse at 3 months and subsequent disease detection by 12 months. There were 8 discontinuations before Treatment Group the 24-month follow-up (6 deaths, 3 in each group, and 2 MAL-PDT Surgery withdrawn consents in the methyl aminolevulinate PDT Characteristic (n = 52) (n = 49) group). Six patients, 4 in the methyl aminolevulinate PDT Sex, No. M/F 32/20 29/20 group and 2 in the surgery group, did not attend their 24- Race, No. (%) white 52 (100) 48 (98) month follow-up visits (Figure 1). Age, mean (range), y 69 (40-95) 67 (38-82) Skin type (Fitzpatrick score), LESION CLEARANCE No. (%) I 4 (8) 4 (8) II 26 (50) 21 (43) Three months after the last PDT treatment or surgery, 48 III 21 (40) 21 (43) (91%) of 53 lesions treated with methyl aminolevulinate IV 1 (2) 3 (6) PDT and 51 (98%) of 52 lesions treated with surgery showed No. of lesions per patient, a complete clinical response. When center differences were No. (%) accounted for by means of a Mantel-Haenszel analysis, the 1 49 (94) 43 (88) 2 3 (6) 6 (12) estimated treatment difference was 4.8% (95% confi- Total No. of lesions 55 55 dence interval, −3.4% to 13.0%) (P=.25). The upper bound Location of lesions, No. (%)* of the 95% confidence interval was less than 15%, thereby Face/scalp 22 (40) 32 (58) providing support for the hypothesis that methyl ami- Trunk/neck 27 (49) 16 (29) nolevulinate PDT was not inferior to surgery. Lesion re- Extremities 6 (11) 5 (9) sponse rates in each group were high and similar irrespec- Longest lesion diameter, Table 2 No. (%)* tive of the site or size of the lesion ( ). 5-14 mm 42 (76) 44 (80) 15-19 mm 11 (20) 6 (11) 12- AND 24-MONTH DISEASE STATE 20-30 mm 2 (4) 3 (5) Two lesions that appeared completely cleared at 3 months Abbreviation: MAL-PDT, methyl aminolevulinate photodynamic therapy. after methyl aminolevulinate PDT showed evidence of *Location and longest diameter of lesions were not recorded for 2 patients (4%) in the surgery treatment group. disease at 12 months, whereas all lesions cleared by surgery remained disease free at 12 months. The total disease- free response rates at 12 months were 44 (83%) of 53 lesions with methyl aminolevulinate PDT vs 50 [96%] of Table 2. Complete Response to Treatment at 3 Months, 52 lesions (P=.15) (Table 3). At the 24-month assess- Per-Protocol Population, by Size and Location ment, an additional 3 lesions showed evidence of disease after methyl aminolevulinate PDT, while 1 lesion Treatment Group showed evidence of disease after surgery Response MAL-PDT Surgery No. of patients 50 47 COSMETIC OUTCOME No. of lesions 53 52 Overall lesion response, No. (%) 48 (91) 51 (98) Assessment of cosmesis favored methyl aminolevuli- Face/scalp 20/21 (95) 31/32 (97) nate PDT over surgery at all time points, whether rated Trunk/neck 23/27 (85) 15/15 (100) by clinician or subject (Table 4). All preferences were Extremity (including shoulder) 5/5 (100) 5/5 (100) Longest diameter, No. (%) statistically significant (Cochran-Mantel-Haenszel test) 6-14 mm 36/40 (90) 42/43 (98) except for the 3-month assessment by subjects. An ex- 15-19 mm 10/11 (91) 6/6 (100) ample of the response at 12 months is shown in Figure 2. 20-30 mm 2/2 (100) 3/3 (100) None of the patients treated with methyl aminolevulinate PDT had a poor cosmetic outcome as judged by the Abbreviation: MAL-PDT, methyl aminolevulinate photodynamic therapy. investigator or patient, whereas 4 patients in the surgery group had a poor outcome as judged by the inves- aminolevulinate PDT group, 1 patient was a major pro- tigator and 3 patients in this group rated their outcome tocol violator (received a light dose less than that stipu- as poor (Figure 3). lated in the protocol), and 1 patient withdrew and therefore had no assessment of response. In the surgery group, SAFETY AND TOLERABILITY 2 patients were withdrawn and had missing response assessments. Therefore, 97 patients, 50 patients with 53 le- More patients treated with methyl aminolevulinate PDT sions treated with methyl aminolevulinate PDT and 47 pa- than surgery reported adverse events (27/52 [52%] com- tients with 52 lesions treated with surgery, were included pared with 14/49 [29%]) (P=.03, Fisher exact test). This in the 3-month per-protocol analysis population. Eighty- was anticipated because local anesthesia was provided nine patients, 44 patients with 46 lesions in the methyl with surgery, but not with methyl aminolevulinate PDT. aminolevulinate PDT group and 45 patients with 50 le- Most of these adverse events were transient local reac- sions in the surgery group, were assessed for cosmetic out- tions commonly associated with this treatment modal- come at the 12-month follow-up. However, tumor-free re- ity, such as burning sensation of the skin, pain in the skin,

(REPRINTED) ARCH DERMATOL / VOL 140, JAN 2004 WWW.ARCHDERMATOL.COM 20

12 mo After Treatment 24 mo After Treatment

Estimated Estimated MAL-PDT, Surgery, Difference MAL-PDT, Surgery, Difference Response Category No. (%) No. (%) (95% CI) No. (%) No. (%) (95% CI) Nonresponse or 7 (13) 1 (2) 8 (−1 to 18) 10 (19) 2 (4) 8 (−1 to 22) recurrence Tumor free 44 (83) 50 (96) 9 (−3 to 20) 32 (60) 44 (85) 18 (3 to 34) Missing/ 2 (4) 1 (2) NA 11 (21) 6 (11) NA discontinued Total No. of Lesions 53 52 NA 53 52 NA

Abbreviations: CI, confidence interval; MAL-PDT, methyl aminolevulinate photodynamic therapy; NA, not applicable. *Three patients in each group died; in addition, 2 patients in the MAL-PDT group withdrew their consent to participate in the trial. Six patients with 9 lesions (6 in the MAL-PDT group and 3 in the surgery group) did not attend the 24-month follow-up visit.

Table 4. Excellent or Good Cosmetic Outcome Over Time* A

Treatment Group, No. (%) Time From Last Treatment, mo MAL-PDT Surgery P Value Investigator Rated 3 36/44 (82) 15/45 (33) .001 12 33/42 (79) 17/45 (38) .001 24 24/29 (83) 16/39 (41) .001 Patient Rated 3 39/41 (95) 37/44 (84) .10 12 41/42 (98) 36/43 (84) .03 24 28/29 (97) 27/36 (75) .04

Abbreviation: MAL-PDT, methyl aminolevulinate photodynamic therapy. *Cochran Mantel-Haenszel test showed a significant difference in favor of MAL-PDT at all time points for the investigator ratings and at 12 and 24 B months for the patient ratings. See “End Point Assessments” subsection of the “Methods” section for explanation of rating scale.

or erythema (Table 5). One patient in the methyl aminolevulinate PDT group discontinued treatment because of a severe burning sensation of the skin; the pain resolved later that day without medical intervention. All other local adverse events were of mild to moderate intensity, and all resolved in less than 1 day. Three patients had skin infections after surgery; there Figure 2. A male patient with a nodular basal cell carcinoma on the forehead, in were no infections in the methyl aminolevulinate PDT facial (A) and close-up (B) view (scale in millimeters). The untreated lesion is group. Three patients died during the first 12 months of shown on the left, while on the right, complete clinical response with no scar- the study; 1 patient treated with methyl aminolevulinate ring is seen at 12 months after methyl aminolevulinate photodynamic therapy. PDT had a fatal myocardial infarction after removal of a kidney tumor, and 2 patients treated with surgery died of linate PDT is as effective as excision surgery, in terms of myocardial infarction. In each case, the cause of death was clinical complete response rate at 3 months (91% vs 98%, considered unrelated to the study treatment. An addi- respectively). It should be noted that the study was pow- tional patient treated with surgery was hospitalized after ered to detect a 15–percentage point difference at 3 months, confirmation of breast carcinoma and underwent a total and therefore smaller differences in response, which might right mastectomy with lymph node clearance. still be important to some clinicians, will not be apparent. The confidence interval was wider for tumor-free rate at COMMENT 12 months, and at this time a 15–percentage point advantage in favor of surgery cannot be excluded. This, to our knowledge, is the first prospective, random- Topical PDT is generally reported to be nonscarring ized study to compare treatment of primary nodular BCC or minimally scarring, but formal evaluation of cosmetic with topical PDT and simple excision surgery, convention- outcome of PDT against standard excision surgery has not ally regarded as the treatment of choice.5,6 The results of previously been reported. Assessments made by both pa- the study support that treatment with methyl aminolevu- tient and investigator showed that more patients achieved

(REPRINTED) ARCH DERMATOL / VOL 140, JAN 2004 WWW.ARCHDERMATOL.COM 21

MAL-PDT, % of Patients MAL-PDT, 20

40 Surgery, % of Patients Surgery, 20

0 Excellent Good Fair Poor Excellent Good Fair Poor

Figure 3. Cosmetic outcome at 3, 12, and 24 months on investigator and patient assessment. MAL-PDT indicates methyl aminolevulinate photodynamic therapy.

ing between investigators and patients may be attribut- Table 5. Adverse Events to Treatment able to the investigators’ assessment being based on detailed evaluation of treatment site characteristics, including pres- Treatment Group, No. (%) ence or absence of a scar, while patients gave a global as- MAL-PDT Surgery sessment. Patient evaluation clearly has priority over un- (n = 52) (n = 49) blinded investigator assessment, although the overall Any adverse event 27 (52) 14 (29) conclusions are the same. Interestingly, it can also be seen Total No. of adverse events 61 24 (Figure 3) that many more subjects scored their cosmesis Any local adverse event as the highest (excellent) grade with methyl aminolevu- First cycle, first treatment 20/52 (38) 8/49 (16) linate PDT than with surgery. Given the importance of First cycle, second treatment 18/49 (37) NA avoidance of scarring caused by the treatment of BCC, Second cycle, first treatment 1/12 (8) NA 5 Second cycle, second treatment 3/10 (30) NA which predominantly occurs on exposed sites, methyl ami- Common local adverse events* nolevulinate PDT may have an important advantage over Burning sensation of skin 16 (31) 0 surgery for some patients. Pain in skin 7 (14) 3 (6) At 24 months, 5 recurrences of previously cleared Erythema 7 (14) 1 (2) lesions were seen in the methyl aminolevulinate PDT Skin infection 0 3 (6) group vs 1 in the surgical group. The study was not pow- Crusting 2 (4) 0 Itching 2 (4) 0 ered to examine long-term recurrence rate, but the find- ings were consistent with previous reports for these re- 17-20 17 Abbreviations: MAL-PDT, methyl aminolevulinate photodynamic therapy; spective treatments. Soler et al reported a recurrence NA, not applicable. rate of 8% at 1 year, after combined treatment of lesions *Reported by more than 1 patient. with debulking followed by single 5-aminolevulinic acid PDT. More recently, Wang et al20 reported a clinical re- an excellent or good cosmetic result with methyl ami- currence rate of 5% at 1 year for single 5-aminolevulinic nolevulinate PDT than surgery (Figure 2). Even at 2 years, acid PDT treatment, but the histologically confirmed re- allowing time for full healing after surgery, 97% of pa- currence rate was higher at 25%. A recent retrospective tients receiving methyl aminolevulinate PDT assessed their study of recurrence of superficial and nodular BCC after outcome as excellent or good, compared with 75% after 2 methyl aminolevulinate PDT treatments, involving a surgery (P=.04), while the corresponding investigator as- mean follow-up of 35 months (range, 2-4 years), showed sessment was 83% vs 41% (P=.001). Differences in scor- that 89% of a total of 310 lesions remained in complete

(REPRINTED) ARCH DERMATOL / VOL 140, JAN 2004 WWW.ARCHDERMATOL.COM 22

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 response.15 Although recurrence rates tend to be higher at the American Academy of Dermatology; March 23, 2003; with PDT than surgery, methyl aminolevulinate PDT is San Francisco, Calif. a relatively tumor-selective therapy that conserves nor- We acknowledge the following investigators for pro- mal skin; hence, treatment may be repeated or other treat- viding patients for this study: Nicole Basset-Seguin, MD, St ment options used in the event of a recurrence. Louis Hospital, Paris; Christophe Bedane, MD, Dupuytren Treatment with methyl aminolevulinate PDT addi- Hospital, Limoges, France; Magali Segard, MD, Claude Hu- tionally offers the advantage over surgery of being a rela- riez Hospital, Lille, France; and Michele Delaunay, MD, St tively simple procedure that, with appropriate training, can Andre Hospital, Bordeaux, France. be performed by a specialist nurse.9 Relative costs com- Corresponding author and reprints: Lesley E. Rhodes, pared with surgery are outside the scope of this report and MD, FRCP, Photobiology Unit, Dermatology Centre, Uni- will vary according to local factors such as category of per- versity of Manchester, Clinical Sciences Building, Hope Hos- sonnel performing PDT, cost of purchase or hire of illu- pital, Salford M6 8HD, England. mination equipment, and surgeon costs,9 in addition to number of PDT treatments required. In this study, accept- REFERENCES able clearance outcomes were achieved after a cycle of 2 PDT treatments in the majority of lesions, although a sig- 1. Slaper H, Velders GJM, Daniel JS, de Gruijl FR, van der Leun JC. Estimates of nificant proportion of tumors (13/55 [24%]) required 2 ozone depletion and skin cancer incidence to examine the Vienna Convention achievements. Nature. 1996;384:256-258. cycles, ie, 4 PDT treatments. The treatment therefore ap- 2. Scott J, Fears TR. Incidence of Non-melanoma Skin Cancer in the United pears most appropriate for patients who value excellent States. Washington, DC: National Institutes of Health; 1981. NIH publication cosmetic outcome over the inconvenience of making ad- 82-2433. 3. Green A, Battistutta D, Hart V, Leslie D, Weedon D, for the Nambour Study Group. ditional visits to the clinic, or where avoidance of an in- Skin cancer in a subtropical Australian population: incidence and lack of asso- vasive procedure is an important factor. Unlike surgery, ciation with occupation. Am J Epidemiol. 1996;144:1034-1040. there is no routine need for local anesthesia. Methyl ami- 4. Marks R. The epidemiology of non-melanoma skin cancer: who, why and what can we do about it. J Dermatol. 1995;22:853-857. nolevulinate PDT is well tolerated; in this study, adverse 5. Thissen MRTM, Neumann MHA, Schouten LJ. A systematic review of treatment mo- events were consistent with the profile of adverse events dalities for primary basal cell carcinomas. Arch Dermatol. 1999;135:1177-1183. 6. Telfer NR, Colver GB, Bowers PW. Guidelines for the management of basal cell previously reported with PDT using topical 5-aminolevu- carcinoma. Br J Dermatol. 1999;141:415-423. 17,20-23 15 linic acid and topical methyl aminolevulinate, ie, 7. Hsi RA, Rosenthal DI, Glatstein E. Photodynamic therapy in the treatment of can- generally of mild to moderate intensity, and resolving the cer. Drugs. 1999;57:725-734. 8. Kennedy JC, Pottier RH, Ross DC. Photodynamic therapy with endogenous pro- same day without the need for medical treatment. toporphyrin IX: basic principles and clinical experience. J Photochem Photobiol In conclusion, this study supports that treatment of B. 1990;6:143-148. primary nodular BCC with methyl aminolevulinate PDT 9. Morton CA, Brown SB, Collins S, et al. Guidelines for topical photodynamic therapy. Br J Dermatol. 2002;146:552-567. is effective and has cosmetic advantages over surgery. Long- 10. Peng Q, Warloe T, Berg K, et al. 5-ALA based photodynamic therapy. Cancer. term follow-up is advised in view of the trend for higher 1997;79:2282-2308. 11. Haller JC, Cairnduff F, Slack G, et al. Routine double treatments of superficial recurrence rate. Since topical methyl aminolevulinate PDT basal cell carcinomas using aminolaevulinic acid–based photodynamic therapy. has recently become licensed for the treatment of nodular Br J Dermatol. 2000;143:1270-1274. BCC in 14 countries, experience with this new agent con- 12. Peng Q, Moan J, Warloe T, et al. Build-up of esterified aminolevulinic-derivative– induced porphyrin fluorescence in normal skin. J Photochem Photobiol B. 1996; tinues to grow. Methyl aminolevulinate PDT is a promis- 34:95-96. ing treatment option in nodular BCC that may have par- 13. Kloek J, Beijersbergen van Henegouwen MJ. Prodrugs of 5-aminolevulinic acid ticular application when avoidance of scarring is a priority. for photodynamic therapy. Photochem Photobiol. 1996;64:994-1000. 14. Fritsch C, Homey B, Stahl W, Lehmann P, Ruzicka T, Sies H. Preferential relative porphyrin enrichment in solar keratoses upon topical application of 5-aminolevu- Accepted for publication April 8, 2003. linic acid methylester. Photochem Photobiol. 1998;68:218-221. 15. Soler AM, Warloe T, Berner A, Giercksky KE. A follow-up study of recurrence From the Departments of Dermatology, Royal Liver- and cosmesis in completely responding superficial and nodular basal cell car- pool University Hospital, Liverpool, England (Drs Rhodes cinomas treated with methyl 5-aminolaevulinate–based photodynamic therapy and Wong), Academic Medical Centre, Amsterdam, the Neth- alone and with prior curettage. Br J Dermatol. 2001;145:467-471. 16. National Cancer Institute. National Cancer Institute Common Toxicity Criteria. Ver- erlands (Dr de Rie), and Norra A¨ lvsborgs La¨nssjukhus, Troll- sion 2.0. Bethesda, Md: National Cancer Institute; 1999. ha¨ttan, Sweden (Dr Enstro¨m); Centre of Dermatology, Uni- 17. Soler A, Warloe T, Tausjø J, Berner A. Photodynamic therapy by topical aminolevulinic acid, dimethylsulphoxide and curettage in nodular basal cell carci- versity College London, London, England (Dr Groves); noma: a one-year follow-up study. Acta Derm Venereol. 1999;79:204-206. Departments of Dermatology, Haukeland Hospital, Ber- 18. Rowe DE, Carroll RJ, Day CL. Long-term recurrence rates in previously untreated gen, Norway (Dr Morken), Leeds General Infirmary, Leeds, (primary) basal cell carcinoma. J Dermatol Surg Oncol. 1989;15:315-328. 19. Silverman MK, Kopf AW, Bart RS, Grin CM, Levenstein MS. Recurrence rates of England (Dr Goulden), Hoˆpital Sainte-Marguerite, Mar- treated basal cell carcinomas. J Dermatol Surg Oncol. 1991;17:713-718. seille, France (Dr Grob), University Hospital of Wales, Car- 20. Wang I, Bendsoe N, Klinteberg C, et al. Photodynamic therapy versus cryosur- diff, Wales (Dr Varma), and University of Graz, Graz, Aus- gery of basal cell carcinomas. Br J Dermatol. 2001;144:832-840. 21. Szeimies RM, Karrer S, Sauerwald A, Landthaler M. Photodynamic therapy with tria (Dr Wolf); and Photobiology Unit, Dermatology Centre, topical application of 5-aminolevulinic acid in the treatment of actinic keratoses: University of Manchester, Hope Hospital, Salford, En- an initial clinical study. Dermatology. 1996;192:246-251. 22. Jeffes EW, McCullough JL, Weinstein GD, et al. Photodynamic therapy of ac- gland (Dr Rhodes). tinic keratosis with topical 5-aminolevulinic acid: a pilot dose-ranging study. Arch This study was supported by a financial grant from Pho- Dermatol. 1997;133:727-732. toCure ASA. 23. Fink-Puches R, Hofer A, Smolle J, Kerl H, Wolf P. Primary clinical response and long-term follow-up of solar keratoses treated with topically applied 5-aminolevu- An abstract of this study was presented at the World linic acid and irradiation by different wave bands of light. J Photochem Photo- Congress of Dermatology; July 2, 2002; Paris, France; and biol B. 1997;41:145-151.

(REPRINTED) ARCH DERMATOL / VOL 140, JAN 2004 WWW.ARCHDERMATOL.COM 23