Real-life practice study of the clinical outcome and cost-effectiveness of photodynamic therapy using methyl aminolevulinate (MAL-PDT) in the management of actinic keratosis and basal cell carcinoma

ARTICLE

Auteur(s) : Lieven Annemans^1,2, Karin Caekelbergh², Rik Roelandts³, Hugo Boonen⁴, Christoph Leys⁵, Arjen F Nikkels⁶, V van Den Haute⁷, L van Quickenborne⁸, Evelien Verhaeghe⁹, Bernard Leroy¹⁰

¹Faculty of Medicine, University of Ghent, De Pintelaan 185, 9000 Ghent, Belgium
²IMS Health, Brussels, Belgium
³Universitaire Ziekenhuizen, Leuven, Belgium
⁴H. Hart, Mol, Belgium
⁵ULg University, Liège, Belgium
⁶Klinik St Jozef, Saint Vith, Belgium
⁷Clinique 2 Alice, Uccle, Belgium
⁸A.Z. Sint Lucas, Brugge, Belgium
⁹Universitair Ziekenhuis, Ghent, Belgium
¹⁰Cliniques Universitaires St Luc, Brussels, Belgium

accepté le 22 Avril 2008

Actinic keratosis (AK) is a skin lesion which is induced by prolonged exposure to ultraviolet light. AK lesions can evolve into squamous cell carcinoma and are the most common type of skin lesion with malignant potential. In the Northern hemisphere, AK prevalence is about 11% for adult patients above 21 years old and 25% above 30 [1]. In the UK, AK prevalence was found to be 5.9% in women and 15.4% in men [2]. BCC is the most frequent cutaneous carcinoma (75-80%) [3]. In France, 2 studies found similar results in 2 regions at the end of the 1990s (Champagne-Ardenne and Haut Rhin) with about 120 new cases for 100,000 inhabitants [4]. Statistics from the Belgian Cancer Registry Foundation¹ show an absolute number of 2836 BCC cases recorded for 100,000 inhabitants in the Flemish part of Belgium in 2001. BCC typically occurs in areas of chronic sun exposure. It is usually slow growing and rarely metastasizes, but it can cause clinically significant local destruction and disfigurement if neglected or treated inadequately. Prognosis is excellent with proper therapy.

There are a range of effective treatment options for AK and BCC including cryotherapy, curettage, excision, topical treatments, radiotherapy and photodynamic therapy. There is no one therapy which is found to be perfect for treating AK and BCC, as all have associated drawbacks e.g. poor cosmetic outcome and scarring with cryotherapy, excision and surgery and skin irritation with topical treatments [5-10].

Methyl aminolevulinate (MAL; Metvix^®; Galderma, Lausanne, Switzerland) is a 160 mg.g^–1 topical photosensitiser molecule, application of which results in the selective accumulation of photoactive molecules in the neoplastic tissue. Exposure to red light in the presence of oxygen generates reactive oxygen species which kill neoplastic cells. Healthy surrounding tissue that has not accumulated the photoactive porphyrins is spared.

For the treatment of AK, clinical trials have demonstrated that MAL-photodynamic therapy (MAL-PDT) presented a comparable lesion response rate to that with cryotherapy as well as a superior cosmetic outcome [11-13]. For BCC treatment, clinical trials have shown that MAL-PDT is safe and efficacious and that it is the preferred treatment for patients due to the better cosmetic outcome [14, 15]. In addition, for superficial BCC (sBCC), MAL-PDT offered a lesion response very similar to cryotherapy [16, 17].

Increasingly, pharmacoeconomics is playing an important role in healthcare decision making, alongside the traditional determining factors of safety and efficacy. The prevalence of AK and BCC means that they are very significant in terms of pharmacoeconomics and as a result a number of economic evaluations of treatment of these conditions have been carried out [18-22].

An economic model evaluation of MAL-PDT treatment and a comparator of the management of AK and BCC have been previously published [18]. This model was based on a medical decision tree simulating all possible outcomes associated with the medical decision to apply MAL-PDT or a comparator. The time horizon was 1 year for AK and 5 years for BCC. The comparators were cryotherapy in AK and excision surgery in BCC. Clinical data were obtained from the phase III programme. For AK, data used were from a large multicentre randomised phase III clinical study which compared MAL-PDT with cryotherapy and placebo [12]. In this trial, 89% of the lesions were treated with a complete cycle of MAL-PDT (two sessions, seven days apart) whilst the remaining 11% received only one session. For BCC the data used in the model were taken from two large, prospective, open, randomised comparative multicentre phase III trials, one which included primary superficial BCC (sBCC) lesions [16] and one primary nodular BCC (nBCC) lesions [17]. In the study on sBCC, each patient received one treatment session followed three months later by a cycle of 2 sessions if the response was incomplete. In the study on nBCC, each patient received a cycle of 2 sessions followed 3 months later by a second cycle in the case of incomplete response. For the model, unit costs for all interventions, investigations, medication and medical visits were derived from the official listings of the Belgian Health Insurance (2002).

The model economic evaluation concluded that for treatment of AK, the cost per full responder is comparable to cryotherapy over a one-year period. For BCC, MAL-PDT is better value for money than excision surgery with a cost per full responder lower for nBCC and sBCC over a 5-year period.

The purpose of the present study was twofold. Firstly, the design of this real-life practice study allowed verification of the results obtained in previous randomised clinical trials (RCT). Secondly, from this real-life data the actual cost of treatment of AK and BCC with MAL-PDT could be calculated and used to verify the predictions made with the model-based economic evaluation of the treatment.

Materials and methods

Patients

• – Thin or non hyperkeratotic and non pigmented AK lesions of the face or scalp, and at the same time: a treatment by cryotherapy or 5-FU (fluorouracil) was shown to be insufficient, or the patient presented at least 10 lesions, or recurrent lesions.
• – Superficial and/or nodular BCC for which other available therapies were not adapted because of safety concerns and/or poor cosmetic results such as: lesions on the middle part of the face or on the ears, lesions on skin severely damaged by the sun, widely spread lesions (more than 10 mm in diameter), recurrent lesions

Potential patients were excluded from the study if they were under 18-years-old, pregnant or lactating, already participating in a clinical trial or had contra-indications to the study treatment.

Study procedures

• – Pre-treatment patient information: Patient demography, baseline lesion characteristics, previous therapy, number of pre-treatment consultations and investigations (e.g. biopsies).
• – Information about the MAL-PDT: Lesion preparation, quantity of MAL-PDT used (mg and pricing units, where 1 pricing unit = 200 mg of cream), application time, illumination time, number of consultations during treatment, concomitant therapies, anaesthesia used, tolerability (adverse events).
• – Post treatment patient information (data collected until end of follow up period, 6 months from first MAL-PDT application): Patient clinical response, cosmetic outcome (assessed by physicians), subsequent treatment, number of post treatment consultation and investigations, tolerability.

Outcomes

Clinical outcomes

• – Clinical response was to be characterised as either complete (complete disappearance of the lesion, assessed visually and by palpation) or incomplete (incomplete disappearance of the lesion, assessed visually and by palpation).
• – Cosmetic outcome was classified as excellent (no scarring, atrophy or induration and no or slight occurrence of redness or change in pigmentation compared to adjacent skin); good (no scarring, atrophy or induration, but moderate redness or change in pigmentation compared to adjacent skin); fair (slight to moderate occurrence of scarring, atrophy or induration) or poor (extensive occurrence of scarring, atrophy or induration).

Adverse events including skin discomfort were recorded in order to assess patient tolerability of MAL-PDT treatment.

Health economic outcomes

The average cost of MAL-PDT treatment was calculated based on the number of visits and diagnostic techniques performed during the study period, the quantity of MAL-PDT used during treatment and the cost of reimbursable concomitant therapies. The costs were calculated by multiplying each item of resource use with its unit cost from the health care payer’s perspective, i.e. the Belgian public health insurance Rijksinstituut voor Ziekte- en Invaliditeitsverzekering/Institut National d’Assurance Maladie (RIZIV/INAMI). For the unit costs, a weighted average cost (VIPO/Non-VIPO, VIPO being a French abbreviation for widowed, invalid, pensioner or orphan) was taken, considering that the study population consisted of 68.4% of patients > 65 years of age.

In the original model [18] the resource “medical act” was included in the evaluation. The term medical act in this situation describes ablation or destruction of a superficial benign or malignant tumour of the skin by any procedure (surgical without stitching, electrocoagulation or any other procedure). This resource was not reported by the investigators during this real-life practice study. Discussion with participating investigators revealed that in actual fact this cost should be applied at least once per patient during MAL-PDT treatment, but had not been recorded because in Belgium there is no cost coding for such an act so the investigators had not acknowledged it. It was therefore agreed that the cost for “medical act” was to be included in the cost per lesion calculations.

Comparison of cost calculated from present study with costs from previous model

Statistical methods

Results

Study population

Fifteen patients (13%) with AK and 14 patients (11%) with BCC were lost to follow-up. Two patients withdrew from the study prematurely due to non serious adverse events, one because of oedema, erythema, severe crust forming and pain and one because of severe crust forming.

Baseline disease characteristics

Actinic keratoses

Approximately one third of AK lesions were described as “primary lesions”, i.e. had not yet been treated or cured. The remaining two thirds were “recurrent lesions” i.e. lesions cured by previous therapy (e.g. excision, elecrosurgery, cryotherapy, 5-FU, imiquimod) but subsequently recurred.
Table 1 Baseline lesion characteristics

Basal cell carcinoma

Treatment

Patients had an average of 2 MAL-PDT sessions. On average 8.0 pricing units of MAL-PDT were used over the treatment sessions (AK: 9.6, BCC: 6.7 pricing units). Lesion preparation (debulking, curettage, etc.) before MAL-PDT treatment was performed in 93% of the lesions. Mean time between first and second treatment session was 22 days. Mean time between second and third treatment session (when applicable) was 33 days. The average duration of application time of MAL-PDT was 3 hours. Average illumination time after MAL-PDT application was 9 minutes. Patients had on average 1 follow-up visit during the 6 months after the first MAL-PDT session (table 2).
Table 2 Frequency of consultations and diagnostic biopsies, number of pricing units used, application time for MAL-PDT and illumination time (N = 247)

Clinical response

Cosmetic outcome

In the observational study, 95% of the patients obtained good or excellent cosmetic outcome after MAL-PDT treatment for AK compared to 98% patients in the RCT [12].

For BCC, the cosmetic outcome results obtained from the present observational study were slightly better than those from the RCTs; 94% of the patients with sBCC and 89% of the patients with nBCC had a good to excellent cosmetic outcome in the observational study compared to 89% and 82% respectively in the two RCTs [16, 17].

Subsequent therapies

Concomitant therapy

Adverse events

Cost of MAL-PDT

Cost for actinic keratoses treatment

The cost per lesion was calculated for both the model and the observational data (table 5). The total cost per AK lesion was calculated to be €58.16 in the real-life study and €58.70 from the model.
Table 4 Cost of care AK, BCC, nBCC and sBCC in Euros (health care insurance perspective)

^**1 unit = 200 mg.

For concomitant therapy, only total cost is presented. Only a small part of the concomitant therapy was reimbursable which explains the low amount.

Table 5 Total cost of care and cost per lesion for observational study and model data for AK, nBCC and sBCC

Cost for basal cell carcinoma treatment

The cost per lesion for nBCC and sBCC was calculated from both the model data and the observational data (table 5). The total cost per lesion for nBCC predicted by the model (€260.28) was 17.5% lower than that calculated using the real-life data (€315.69). The total cost per lesion for sBCC predicted by the model (€209.83) was 18.1% higher than in the real-life study (€177.62).

In order to assess the impact of sBCC lesion size on treatment cost, we calculated the cost per lesion and per lesion size on a sub-group of patients with only one sBCC lesion and for whom lesion size was available (64/101, 63.4%). The cost per lesion, irrespective of lesion size, was 284.29 €, which is unsurprisingly higher than in the whole sBCC population, where the mean sBCC number per patient is 1.9, given that some sub-costs (e.g. consultation costs) are spread out among several lesions. The cost per lesion was 250.57 € for lesions in which the size (largest diameter) is < 15 mm (38/64, 53.4%), 332.18 € for lesions in which the size is comprised between 15 mm and 20 mm (15/64, 23.4%) and 335.47€ for lesions in which the size is > 20 mm (11/64, 17.2%).

Discussion

This study also confirmed that MAL-PDT is well tolerated for both AK and BCC. The fact that only 2 of the 247 patients withdrew from this study due to adverse events shows that MAL-PDT is well tolerated in real-life practice, whereas it has been shown that a high rate of non-compliance is associated with the onset of undesirable adverse events for other topical treatments of AK [24]. Fewer AEs were reported in patients with AK in the present study than in the RCT [12] (62% compared to 73% respectively), which indicates that for AK treatment, tolerability in real-life practice is slightly better than that suggested by clinical trials. For BCC, the number of AEs reported in this real-life study was closely comparable to the RCTs [16, 17].

For both this study and the model, cost calculations were based upon 2 sessions of MAL-PDT treatment for AK. However, based on recent data [25], in Belgium the recommended dose is now one initial treatment followed by a subsequent treatment 3 months later if the clinical response is incomplete. The real-life treatment cost for AK could thereby be lower than that calculated from this study and could compare even more favourably with comparator treatments e.g. cryotherapy, on condition that the effectiveness is not compromised by the new schedule.

The treatment cost per AK lesion of MAL-PDT in this real-life study was almost identical to that predicted by the model data (€58.16 and €58.70 respectively). For nBCC and sBCC, costs per lesion calculated from the real-life data were within 20% of the models predicted costs. Thus, in terms of cost per lesion, the real-life data confirmed the predictions made by the model, adding to the predictive validity of the model.

However, the total cost of care calculated for AK was notably higher in the real-life study (€380.66) than the model (€248.86). One explanation is that the patients in the real-life study had an average of approximately 7 AK lesions, compared to an average of only 4 lesions in patients in the RCT from which the model cost was derived [14]. It should also be noted that, for the purpose of cost calculations, the patients described as having >10 lesions by investigators (55% of AK patients) were assumed to have 11 lesions. This estimate is likely to have been conservative as at least some of these patients are likely to have had more than 11 lesions.

In addition, the Belgian reimbursement criteria, which were used as inclusion criteria for the real-life study, required that eligible AK patients should have had more than 10 lesions, recurrent lesions or have been unsuccessfully treated with cryotherapy. Considering that recurrent AK lesions are harder to treat than primary lesions and that 67% of AK lesions were recurrent, one can conclude that the Belgian reimbursement criteria only allow “difficult-to-treat” AK patients to receive MAL-PDT.

The total cost of treatment and the cost per lesion were higher for nBCC than for sBCC in both the model and this real-life study. This can be explained by a greater number of consultations and a greater quantity of MAL-PDT used for treating nBCC than sBCC.

The real-life cost of care was €40 higher than the model prediction for nBCC, and €70 higher for sBCC. However, the MAL-PDT cost per full responder being lower than the cost of the comparator for treatment of nBCC and sBCC, excision surgery [14], it still remains cost effective.

One issue with pharmacoeconomic evaluations is the problem of how results can be extrapolated to be relevant in different countries and to different healthcare providers. In order to allow generalisation of results, the major factors to be considered are the unit costs of treatment, the volume of drug used (dependent on the recommended treatment regimen) and the resource use (e.g. physician time vs nurse time, specialist vs GP). Considering that in Belgium MAL-PDT can only be administered by a dermatologist within a hospital setting, and that the AK lesions treated with MAL-PDT are, by their nature, harder to treat, it could be considered that costs elsewhere in the world are likely to be similar to, or lower than, those found in this study. The fact that this real-life study has confirmed the predictions of the model means that the same model could be used to evaluate the cost-effectiveness of MAL-PDT in other healthcare settings, provided that the appropriate clinical information is available.

Conclusion

The costs calculated from this real-life practice study confirm the predicted cost-effectiveness shown in the original model for MAL-PDT in the management of AK and BCC.

Acknowledgements

References

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1 http://www.registreducancer.be.