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Photodynamic Therapy of Multiple Nonmelanoma Skin Cancers With Verteporfin and Red Light–Emitting Diodes
Two-Year Results Evaluating Tumor Response and Cosmetic Outcomes
Harvey Lui, MD;
Lori Hobbs, MD;
Whitney D. Tope, MPhil, MD;
Peter K. Lee, MD, PhD;
Craig Elmets, MD;
Nathalie Provost, MD;
Agnes Chan, PhD;
Herma Neyndorff;
Xiang Yao Su, PhD;
Hem Jain, MD;
Iltefat Hamzavi, MD;
David McLean, MD;
Robert Bissonnette, MD
Arch Dermatol. 2004;140:26-32.
ABSTRACT
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Background Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge.
Objective To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers.
Design Open-label, randomized, multicenter, dose-ranging phase 2 study conducted at 4 North American university-based dermatology clinics.
Patients Fifty-four patients with 421 multiple nonmelanoma skin cancers including superficial and nodular basal cell carcinoma and squamous cell carcinoma in situ (Bowen disease).
Methods A single intravenous infusion of 14 mg/m2 of verteporfin followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm2 of red light (688 ± 10 nm) from a light-emitting diode panel.
Main Outcome Measures Pathologic response of treated sites was assessed at 6 months. Clinical and cosmetic responses were assessed and graded at 6 weeks, 3 months, and 6 months after verteporfin PDT, with optional follow-up visits at 12, 18, and 24 months.
Results The histopathologic response, defined as absence of tumor on biopsy specimens 6 months after verteporfin PDT, ranged from 69% at 60 J/cm2 to 93% at 180 J/cm2. At 24 months of follow-up (276 tumors in 31 patients), the clinical complete response rate ranged from 51% at 60 J/cm2 to 95% at 180 J/cm2. No significant systemic adverse events were observed; most events occurred at the treated tumor sites and included events such as pain. Overall, 65% (95% confidence interval, 58%-71%) of tumors were judged to have good to excellent cosmesis at 24 months.
Conclusion A single course of verteporfin PDT showed treatment benefit for patients with multiple nonmelanoma skin cancers.
INTRODUCTION
Nonmelanoma skin cancers (NMSCs) are the most common carcinomas affecting men and women, with about 1.3 million cases reported annually in the United States.1 Basal cell carcinoma (BCC) accounts for approximately 75% of NMSC and 25% of all cancers diagnosed in the United States, whereas squamous cell carcinoma (SCC) accounts for 20% of NMSC.2
Photodynamic therapy (PDT) is a 2-step process consisting of administration of a photosensitizer followed by light application.3 Verteporfin (benzoporphyrin derivative monoacid A ring), is a semisynthetic, second-generation porphyrin derivative that can be activated by red light (peak absorption, 689 nm). This wavelength permits activation of the drug within the deep portions of tumors. For the treatment of NMSC with verteporfin PDT, light-emitting diodes (LEDs) can be used as the red light source.
The present study examines pathologic, clinical, and cosmetic outcomes for patients with multiple NMSCs who underwent verteporfin PDT using LED light. The cosmetic assessments performed in this study are unique in that they were prospectively defined, semiquantitative, and conducted periodically for up to 2 years after treatment.
METHODS
STUDY PATIENTS AND RANDOMIZATION
Patients with at least 2 biopsy-proven nonpigmented NMSCs (either superficial or nodular BCC or SCC in situ [Bowen disease]) were recruited for this study (Table 1). All patients gave written informed consent, and approval from each participating institution's ethics committee or institutional review board was granted before the beginning of the study.
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Table 1. Tumor Characteristics
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Patients were randomly assigned to receive 1 of 3 different light doses: 60, 120, or 180 J/cm2. If a second treatment was required, the patient's light dose remained the same as that given in the first course. To avoid a marked difference in the number of tumors within each treatment group, randomization was stratified by the number of tumors (2-5 tumors, 6-10 tumors, or >10 tumors) and by center.
PDT WITH VERTEPORFIN
Patients received a 10-minute intravenous infusion of 14 mg/m2 of verteporfin (QLT Inc, Vancouver, British Columbia) followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm2 of red light (688 ± 10 nm) from a nonthermal LED panel. Up to 20 tumors were exposed to light in 1 session. The exposed area included a peritumoral margin of 3 to 4 mm. Tumors that could not be treated within the 1- to 3-hour postinfusion time window could receive other standard therapy at the discretion of the investigator. These tumors were not included as part of this study.
Tumors could be retreated at 3 months after the initial treatment if the investigator judged that the tumor had not achieved a clinical complete response (CCR). For retreatment, the verteporfin dose was increased to 18 mg/m2, but the patient's light dose remained the same as that used in the first course.
LIGHT DELIVERY DEVICES
The LED panels consisted of a monolithic array of hybrid gallium aluminum arsenide LEDs that emitted diffused red light (Quantum Devices Inc, Barneveld, Wis). A photograph of the LED unit and treatment head is provided in Figure 1. The LED panel had a central wavelength of 688 ± 10 nm, with a full-width half-maximum bandwidth of approximately 25 nm. The emission spectrum of the LED unit compared with the absorption spectrum of verteporfin is illustrated in Figure 2. The irradiance delivered to the skin by the LED unit was 200 ± 40 mW/cm2. The LED output was checked by a radiometer (model UDT268M; UDT Instruments, Baltimore, Md) before and after the tumors were exposed to light.
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Figure 1. Light-emitting diode (LED) unit with a close-up of LED treatment head (inset).
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Figure 2. Graphic comparison of the emission spectrum of the light-emitting diode unit used in this study and the absorption spectrum of verteporfin.
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OUTCOME MEASURES
Response
The primary efficacy variable was the histopathologic response (HPR) rate, defined as the percentage of treated tumor sites with no residual tumor as assessed by a histopathologic review of a representative 2-mm punch biopsy specimen taken from within the PDT treatment site 6 months after the first verteporfin PDT course. Retreated tumors were included in the calculation of the HPR rate. Clinical response of the treated sites was assessed at 6 weeks and 3, 6, 12, 18, and 24 months after verteporfin PDT. Follow-up beyond 6 months was optional. The CCR rate was defined as the percentage of treated sites that were judged by the investigator to be tumor free on clinical examination.
Cosmetic Outcome
At each follow-up visit, the color, profile, and texture of each treated site (ie, tumor plus peritumoral margin) were assessed by the investigator and assigned a numeric value depending on the answers to following questions: (1) Are you satisfied with how the color of the scar matches the color of the surrounding skin? (2) Are you satisfied that the scar surface is flush with the surrounding skin? (That is, are you satisfied that the scar surface is not too elevated or depressed with respect to the surrounding tissue?) (3) Are you satisfied with how the surface texture of the scar blends with the surrounding skin? A yes answer was scored 3 points; neutral, 2 points; and no, 1 point. For each treated site, the points of all 3 responses were tallied, and the cosmetic outcome was judged to be excellent (a score of 9), good (7 or 8), satisfactory (5 or 6), or poor (3 or 4).
Investigators also rated the cosmetic outcome of each site treated with verteporfin PDT as superior to, equivalent to, or worse than the cosmetic outcome expected from a standard treatment such as surgical excision or electrodesiccation and curettage. This subjective global assessment was based on the investigators' prior general clinical experiences with cosmetic outcomes for standard treatment of lesions of equivalent location and size. Patients who had received prior standard therapy for skin tumors were also asked to rate the cosmetic outcome of each of their verteporfin-treated sites as superior to, equivalent to, or worse than the cosmetic outcome obtained with a prior standard therapy. Only sites with a CCR were included in this analysis.
STATISTICAL ANALYSIS
All statistical tests and confidence intervals (CIs) were 2-sided with an  of .05. The SAS statistical package (version 8.2) was used for the analyses (SAS Institute Inc, Cary, NC). The 95% CIs were calculated based on the binomial distribution. In addition to the overall response for all tumors combined, the HPR and CCR rates were also determined according to tumor type (nodular BCC, superficial BCC, or SCC), size (<1 cm, 1-2 cm, >2 cm), and location (head and neck, upper extremities, lower extremities, or trunk).
Only observed tumor data were included in the analyses. In addition, the last observation was carried forward for tumors that had been nonresponders at the most recent visit, and values of nonresponders were imputed for tumors that were not assessed because they had received alternate therapy.
To adjust for correlation among tumor outcomes within a patient, we used the generalized estimating equation (GEE) method4-5 with a robust covariance and an exchangeable working correlation structure to explore the effect of light dose on tumor pathologic response at month 6, clinical response at month 24, and investigator assessment of cosmetic response (excellent or good vs satisfactory or poor) at months 6 and 24. In addition, the effects of age, sex, and tumor size, type, and location were evaluated in the GEE model. The Spearman rank correlation coefficient6 was used to evaluate correlation between investigator and patient assessments of cosmetic outcome compared with previous standard therapy.
RESULTS
Fifty-four patients with 421 tumors received at least 1 course of verteporfin PDT (Table 1). The average number of treated tumors per patient was 7.8 (range, 2-20). Patients ranged in age from 22 to 79 years, with a mean age of 55 years, and most had Fitzpatrick skin phototype II or III. Most tumors (92%) were BCC, and 15 patients had nevoid BCC syndrome. Six patients (31 tumors), all of whom were treated with a light dose of 60 J/cm2, received a second treatment with 18 mg/m2 of verteporfin and the same light dose. Seven patients (51 tumors) withdrew from the study prior to month 6: 2 were lost to follow-up; 4 withdrew for unspecified reasons; and 1 requested withdrawal owing to the inconvenience of travel and treatment site pain requiring the use of codeine. Although the follow-up visits after month 6 were optional, 31 patients (57%) with 276 tumors (66%) were available for a full 2 years of follow-up. The ages, sex distribution, and number and types of tumors were not different between those patients who completed 24 months of follow-up and those who were observed for only 6 months.
HISTOPATHOLOGIC RESPONSE
There was a dose-response relationship of HPR to verteporfin PDT, with HPR rates of 69% (95% CI, 61%-76%), 79% (95% CI, 70%-86%), and 93% (95% CI, 86%-97%) noted for tumors receiving 60, 120, and 180 J/cm2, respectively (n = 378; nonresponse carried forward for 8 tumors). The HPR rates according to tumor type, size, and location are listed in Table 2. The dose response relationship was confirmed by GEE modeling. Although the overall effect of light dose was not significant (P = .06), there was a trend indicating that the higher HPR was associated with a higher light dose. There was no significant difference in HPR rate between age, sex, tumor size, tumor location, and tumor type.
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Table 2. Tumor Histopathologic Response at 6 Months After Verteporfin Photodynamic Therapy*
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CLINICAL COMPLETE RESPONSE
Treatment sites judged to be tumor free based on clinical examination were recorded as CCR. The CCR rate increased with the light dose. At 6 months after verteporfin PDT, the CCR rates were 78% (95% CI, 71%-84%), 88% (95% CI, 81%-94%), and 98% (95% CI, 93%-100%) for tumors treated with 60, 120, and 180 J/cm2, respectively (n = 378); 24 months after verteporfin PDT, the responses were 51% (95% CI, 42%-61%), 79% (95% CI, 67%-88%), and 95% (95% CI, 89%-99%), respectively (n = 276) (Figure 3). At 24 months, the GEE model showed significant differences in CCR between the light doses (180 vs 120 J/cm2, P = .02; 180 vs 60 J/cm2, P<.001; 120 vs 60 J/cm2, P = .05). Other factors such as age, sex, tumor size, tumor location, and tumor type were not predictive of clinical response. In addition, tumors responded similarly in patients with and without nevoid BCC syndrome.
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Figure 3. Clinical complete response (CCR) rate for evaluable tumors over time at indicated photodynamic therapy light doses.
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COSMETIC OUTCOME
The cosmetic outcomes of treated tumor sites as assessed by the investigators at month 24 (categorized as excellent, good, satisfactory, or poor) are presented in Figure 4. The best cosmetic outcomes were observed in tumors treated with 60 J/cm2. The cosmetic outcome of the tumors in the 180 J/cm2 group improved markedly over time (data not shown). The GEE modeling showed significant differences in the cosmetic outcome rate between certain light doses only at month 6 (180 vs 60 J/cm2, P = .001; 120 vs 60 J/cm2, P = .05) and not at month 24. Smaller tumors showed better cosmesis at month 6 (P = .01) and month 24 (P = .02). At month 24, head and neck tumors showed significantly better cosmesis than tumors in other locations (P<.01 for all). An example of an excellent cosmetic outcome is shown in Figure 5.
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Figure 4. Investigator assessment of tumor cosmetic outcome for verteporfin photodynamic therapy at month 24.
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Figure 5. Basal cell carcinoma of the ear before (A) and 24 months after (B) verteporfin photodynamic therapy at 120 J/cm2.
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Investigators and patients were asked to compare the results of verteporfin PDT with prior standard treatments. At month 24, patients assessed the cosmetic outcome of 58% of treated tumors as superior to prior therapy (Figure 6). The percentage of outcomes judged by investigators and patients to be superior to prior therapy was highest at the 60 J/cm2 light dose and lowest at the 180 J/cm2 light dose. Despite slight differences in the numbers of sites assessed, investigator assessments of cosmetic outcome were in agreement with patient assessments at month 6 and month 24 (P<.001).6
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Figure 6. Comparison of patient and investigator assessments of tumor cosmetic outcome for verteporfin photodynamic therapy vs standard therapy at month 24.
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ADVERSE EVENTS
Adverse events associated with treatment occurred in 48 (89%) of 54 patients. In general, verteporfin PDT was well tolerated with no major systemic adverse events. The most common systemic associated adverse events were headache (5 patients, 9%) and photophobia (2 patients, 4%). Most of the associated adverse events occurred at the treatment site.
Discomfort during light treatment was described variously as warmth, pain, burning/stinging, prickling, and pruritus, which in turn were collectively defined as a specific safety variable called the smarting response. To evaluate the smarting response, investigators interviewed the patients during light application to assess the maximum degree of discomfort on a scale of 1 (barely noticeable) to 5 (severe, requiring interruption of light exposure). Overall, warmth and a burning/stinging sensation were the most commonly reported symptoms of discomfort during light exposure of the tumors, reported for 44% and 41% of the treated sites, respectively (n = 421). Severe treatment site smarting responses during light application were reported by 9 patients (17%) overall with no clear-cut dose-response effect (Table 3). Smarting response symptoms were alleviated by interrupting light treatment briefly, applying ice packs locally, or injecting lidocaine into the site (4% of sites received lidocaine).
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Table 3. Summary of Safety Data by Light Dose*
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Treatment site adverse events occurring after verteporfin PDT were reported by 48 (89%) of 54 patients (Table 3) and included pain (n = 39; 72%), pruritus (n = 13; 24%), burning (n = 12; 22%), edema (n = 11; 20%), prickling (n = 9; 17%), erythema (n = 8; 15%), skin hypertrophy (n = 4; 7%), exudate (n = 3; 6%), hyperesthesia (n = 3; 6%), and stinging (n = 3; 6%). In most patients, these events were mild to moderate in intensity.
Twenty patients (37%) used oral analgesic preparations containing opiates (acetaminophen plus codeine) to control treatment site pain occurring after verteporfin PDT (Table 3). The median duration of pain (Table 3) was similar for the 3 groups (9 days for 60 J/cm2; 12 days for 120 J/cm2; and 14 days for 180 J/cm2). The number of severe pain events was higher at the 180 J/cm2 light dose than at the other 2 light doses.
COMMENT
Successful treatment of multiple NMSCs has been previously reported with a number of systemic photosensitizers, including porfimer sodium, hematoporphyrin derivative, tin ethyl etiopurpurin, and metatetrahydroxyphenylchlorin.7-12 One of the problems associated with many of these photosensitizers is prolonged generalized cutaneous photosensitivity that can last for several months.13
Photodynamic therapy with topical photosensitizers such as aminolevulinic acid (ALA) has also been used for the treatment of NMSC with the advantage of inducing photosensitivity only at the application site. Good complete response rates have been reported for the treatment of superficial BCC and Bowen disease; however, the treatment of nodular BCC with ALA PDT has been associated with higher recurrence rates despite the apparently favorable early responses based on clinical assessment.10, 14-20 This higher recurrence rate might be explained by limited penetration of ALA PDT to deeper areas of the tumor.21 Topical methylester ALA has also been approved for use in Europe. Gentle curettage is performed before methylester ALA application to facilitate penetration of the photosensitizer precursor.20, 22-23
Verteporfin, marketed with the brand name Visudyne (Novartis AG, Basel, Switzerland), is now approved in many countries for the treatment of a number of ophthalmologic indications such as age-related macular degeneration. One of the advantages of verteporfin over other systemic photosensitizers is its short photosensitivity period of only a few days.24 In addition, verteporfin can be activated with 688-nm red light, which penetrates deeper into tumors than the 630- to 635-nm light used to activate porfimer sodium and protoporphyrin IX, the endogenous photosensitizer generated by ALA. The LED device used in this clinical study has a number of advantages over other devices such as lasers and filtered broadband lamps for dermatologic PDT: (1) it is simple to use; (2) it does not have special electrical requirements; (3) it is solid-state and therefore reliable; and (4) it emits a narrow wavelength range.
The exact mechanism of action of verteporfin PDT in the treatment of NMSC is not known. Light-activated verteporfin has been shown to induce cytochrome c release from mitochondria followed by caspase 3, 6, 7, and 8 activation culminating in apoptosis.25 The occurrence of apoptosis following verteporfin PDT appears to be a predominant cytotoxic mechanism in vitro, but its relevance to clinical response following treatment of tumors in vivo has not been assessed. In rabbits, endothelial cell and pericyte damage was observed on biopsy specimens taken immediately after verteporfin PDT when exposure to 690-nm red light took place 1 to 5 hours after verteporfin administration.26 At 2 to 24 hours after verteporfin PDT, no epidermal phototoxic reaction was observed, but blood stasis, edema, and dermal-epidermal separation were present. These observations suggest that PDT at 1 to 5 hours after verteporfin administration might target the vascular compartment.
In the present study, the response rate of verteporfin PDT was highest at 180 J/cm2 with a 93% histopathologic response. The analysis of CCR at month 6 and month 24 shows that at the 2 higher light doses, the clinical response was maintained over time. At the highest light dose, the CCR was 98% at month 6 and 95% at month 24, which compares favorably with standard therapies at 24 months. At 60 J/cm2, the CCR decreased from 78% at 6 months to 51% at 24 months, suggesting that this lower light dose did not result in the same sustained CCR achieved at the 2 higher light doses. The post-PDT biopsy specimens were limited to 2 mm to allow us to more easily observe the PDT cosmetic outcomes over 24 months, but this could potentially have introduced a treatment site sampling error that overestimated the HPR rate.
Cosmetic outcomes were generally favorable. There was a significant inverse relationship between light dose and cosmesis at the 6-month assessment. Since the patients in this study had an average of 8 skin tumors, and some had been diagnosed with nevoid BCC syndrome (which can lead to hundreds of tumors in a lifetime), the comparison of cosmesis between verteporfin PDT and prior therapy, although subjective, is relevant. The cosmetic outcomes of verteporfin PDT at 24 months were favorable, and more than 80% of treated sites were considered by both patients and investigators to have a cosmetic outcome equivalent or superior to previous standard therapies for NMSC. Not unexpectedly, small tumors were associated with more favorable cosmetic outcomes, as were head and neck tumors.
Other than headache in 5 patients, no significant pattern of systemic adverse events was observed in association with the study treatment. The smarting sensations of pain, burning/stinging, or warmth that patients reported at the treatment sites during light application were easily alleviated with ice packs or local anesthetic. These symptoms promptly ceased on termination of light exposure. Pain at the treatment sites after verteporfin PDT was reported by most patients and was generally well controlled with oral analgesics. However, severe posttreatment pain was experienced by 35% of patients, and its frequency was highest at the highest light dose. Patients with a higher number of tumors did not necessarily report more intense pain.
In conclusion, verteporfin PDT as a single treatment modality can induce good response rates with favorable cosmesis. Further study in patients with multiple NMSC is warranted.
AUTHOR INFORMATION
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Corresponding author and reprints: Harvey Lui, MD, Division of Dermatology, University of British Columbia, 835 W 10th Ave, Vancouver, British Columbia, Canada V5Z 4E8 (e-mail: hlui{at}interchange.ubc.ca).
Accepted for publication September 24, 2003.
This study was sponsored by QLT Inc, Vancouver, British Columbia.
This study was presented in part at the 11th Annual Meeting of the Photomedicine Society; February 21, 2002; New Orleans, La; and the International Photodynamic Association Eighth World Congress of Photodynamic Medicine; June 8, 2001; Vancouver, British Columbia.
Writing and editing assistance was provided by Christy V. Costello, ELS, and Anne Fisher, MSc, of QLT Inc.
From the Division of Dermatology, University of British Columbia and Vancouver General Hospital, Vancouver (Drs Lui, Hobbs, Jain, Hamzavi, and McLean); Department of Dermatology, University of Minnesota, Minneapolis (Drs Tope and Lee); Department of Dermatology, University of Alabama, Birmingham (Dr Elmets); Division of Dermatology, University of Montreal Hospital Centre, Montreal, Quebec (Drs Provost and Bissonnette); and QLT Inc, Vancouver, British Columbia (Drs Chan and Su and Ms Neyndorff). Drs Lui, McLean, and Bissonnette have served as paid consultants for QLT Inc, Vancouver, British Columbia. Dr Tope was paid by QLT to attend investigators' meetings and to testify for QLT at the US Food and Drug administration on the present data. Drs Chan and Su and Ms Neyndorff are employees of QLT and hold stock and/or stock options in the company. Dr Hamzavi received funds from QLT for travel expenses to an investigators' meeting and to conduct a phase 3 trial related to data in this study.
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