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Photodiagnosis and Photodynamic Therapy (2014) xxx, xxx—xxx
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Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor Yuan-gang Lu MD, Ph.D. ∗, Yuan-yuan Wang 1, Ya-dong Yang 1, Xing-cun Zhang 1, Yang Gao 2, Yang Yang 2, Jun-bo Zhang 2, Guo-ling Li 2 Department of Plastic & Cosmetic Surgery, Research Institute of Surgery, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Daping, Chongqing 400042, PR China
KEYWORDS Topical photodynamic therapy; Aminolevulinic acid; Skin malignant tumor; Surgery
Summary Background: Photodynamic therapy (PDT) is a successful treatment for non-melanoma skin cancers in clinical practice. In China, more and more doctors use PDT to cure the patients with skin cancer, especially in the elder. The purpose of this study was to evaluate the efficacy of topical PDT using aminolevulinic acid (5-ALA) combined with excision in the treatment of skin malignant tumor and its role in surgical improvements. Methods: A total of 58 cases including 32 cases of BCC, 13 cases of Bowen’s disease, 8 cases of Paget’s disease and 5 cases of SCC were included in this study. All cases were treated with topical ALA-PDT after surgery. Each tumor region was irradiated with 120 J/cm2 using a 635-nm laser for 15 min. A total of 3 times of assisted ALA-PDT was applied after surgery. Results: There was no recurrence in 6 months after treatment. Only 5 cases of Paget’s disease and 2 cases of SCC experienced disease recurrence in 1 year. All patients were able to complete the treatment protocol, with well cosmetic results and no moderate adverse reactions. Conclusions: As an assistive therapy after tumor resection, ALA-PDT can reduce the excision range of the tumor lesions. However, its role in the reduction of recurrence rate remains to be further investigated. © 2014 Elsevier B.V. All rights reserved.
∗
Corresponding author. Tel.: +86 23 68757597; fax: +86 23 68757596. E-mail addresses: [email protected] (Y.-g. Lu), [email protected] (Y.-y. Wang), [email protected] (Y.-d. Yang), [email protected] (X.-c. Zhang), [email protected] (Y. Gao), [email protected] (Y. Yang), [email protected] (J.-b. Zhang), [email protected] (G.-l. Li). 1 Tel.: +86 23 68757597; fax: +86 23 68757596. 2 Tel: +86 23 68757590; fax: +86 23 68757596. http://dx.doi.org/10.1016/j.pdpdt.2014.02.006 1572-1000/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Introduction Skin cancer, particularly nonmelanoma skin tumor, frequently occurs in the exposed parts of the body, e.g., head, face, neck and arms. Invasive growth of the tumors results in the local tissue destruction, leading to the disfigurement due to the displacement of surface organs. Traditional surgery, freezing, radiation and chemotherapy have good therapeutic efficacy to the primary malignant tumor of the skin. However, they are traumatic and are prone to scar formation. In addition, these therapies have very limited effect in beauty [1]. With the economic and social development, the pursuit for good appearance becomes higher and higher. People are looking for the tumor therapies that have less recurrence rate, less pain, less side effects, and do not cause resistance after multiple treatments. How to meet the therapeutic requirement of patients with skin malignancies is one of the clinical challenges. Topical photodynamic therapy (PDT) is a treatment in which 5-ALA is distributed to the lesions and then a light source with specific wavelength enters the lesions to selectively destroy these lesions. As a novel therapy, PDT has good selectivity for tumor tissues, does not destroy normal cells and is not limited by the location or size of the skin lesions. In addition, PDT can be used for multiple times without resistance, and scar formation. Thus, PDT has been more and more applied in the treatment of nonmelanoma skin cancers, and even becomes one of the standard treatments [2,3]. Our department admitted a total of 58 cases with malignant skin tumors from January 2009 to December 2011. We used topical PDT combined with excision to treat these patients and reported the results below.
Patients and methods A total of 58 patients (male: 42; female: 16) were diagnosed as skin cancer from January 2009 to December 2011. These patients had an age of 45—81 years old and a disease course of 9 months to 6 years. Lesions were located in the face, the inner canthus, head and tempus, mouth, neck, limbs, abdomen, penis and vulva, etc. Single lesion occurred in 41 cases and multiple lesions occurred in 17 cases. Eighteen cases had a lesion of less than 2 cm in diameter, 25 cases had a lesion between 3 and 4 cm and 15 cases had a lesion of larger than 5 cm. Histological analysis confirmed that 32 cases had basal cell carcinoma, 13 cases had Bowen’s disease, 8 cases had Paget’s disease and 5 had squamous cell carcinoma. All cases had surgical resection of the lesions followed by ALA-PDT. Eighteen cases received ALAPDT after incomplete surgical resection because the cancer is extremely difficult to be cleaned. Patients with photosensitive history, serious system diseases or severe immune dysfunction or suppression were excluded from the study. Photosensitizer (5-ALA, Shanghai Fudan-Zhangjiang Biomedical Corporation, Shanghai, China) was dissolved in 5% Azone and 10% of 5-ALA emulsion was prepared before treatment. Light source was produced by XD-635AB photodynamic laser therapy instrument (Guilin XINGDA photoelectric Medical Devices Co., Ltd., Guilin, China) with an output wavelength of 635 nm, output power of 200 mW/cm2 and energy density of 120 J/cm2 . All patients
signed informed consent. The details of the surgery, PDT indications, treatment principles, efficacy, possible complications and precautions were explained to the patients before treatment. According to the tumor type, incisions were made along the lesion edge (1 mm beyond the margin). The lesions were completely removed in 40 cases from the subcutaneous fat layer, superficial or deep surface of the fascia to the periosteal surface. According to the size and depth of the wound site, we directly sutured or repaired the wound sites by transplanting appropriate flap or skin graft. For the malignant tumors in special positions, the lesions in 18 cases were removed as much as possible under the condition of maintaining key structures. ALA-PDT was performed 1 week after the surgery and a total of 3 times of PDT was applied. The interval between two treatments was two weeks. The treatment regions including operation area outside the edge of 2.0 cm, were infiltrated with azone for 30 min. Then, 10% topical ALA in an oil-in-water emulsion (5% azone) was applied to the skin of therapy area (2.0 cm beyond the visible lesions) for 4h incubation period under a light-shielding dressing. The target regions were irradiated by the laser with a wavelength of 635 nm, the output power of 200 mW/cm2 , light dose 120 J/cm2 and the exposure time of 15 min for each 3 cm2 field. The photosensitizer was freshly prepared with less than 4 h before therapy. After PDT, prednisone (20 mg/d), Ketotifen Fumarate (1 mg, BID) and cold wet dressings for 2 days were applied. Light was strictly avoided for 2 days after treatment. Scratching was avoided during the process of recovery. At 6 months or one year after termination of therapy, the efficacy of treatment and patient satisfaction, including lesion response and cosmetic effect, were investigated. Occurrence of new lesions in the receded areas was considered as recurrence. Patient satisfaction was graded as satisfaction, less satisfaction, and dissatisfaction.
Results In the group with combination of surgery and PDT, visible lesions were completed removed in 40 patients (Fig. 1a—c), while tumors were partially removed in 18 patients due to the special position (in the inner canthus, scrotum, penis, etc.). After three times of PDT, skin lesions were completely receded (Fig. 2a—d). There was no recurrence after 6 months of treatment. In the one-year follow-up, recurrence was observed in 5 cases of Paget’s disease, 2 cases of squamous cell carcinoma. Recurrence was not observed in other types of tumors. The overall one-year recurrence rate was 12.5% (Table 1). At one year after termination of therapy, all patients were satisfied with therapy effects. The recurrence cases received another surgical excision followed by PDT. Mild to moderate pain was commonly experienced during PDT. All patients have a mild local swelling, which was spontaneously receded after 1—2 days. Significant swelling was treated with cold compress. Swelling was lessened and its duration was shortened by follow-up therapies. Some patients had hyperpigmentation after the rash was subsided which faded within 1—2 weeks. No scar formation was found.
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Figure 1 (a) Left facial basal cell carcinoma. (b) Presentations after 5 days of tumor resection. (c) Presentations after 1 year of resection and PDT.
Figure 2 (a) Basal cell carcinoma in the right inner canthal before treatment. (b) Tumors involving the medial canthal tendon and adjacent lacrimal punctum. (c) Tumor resection and autologous transplantation of skin graft. (d) Presentations after 6 months of resection and PDT.
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Y.-g. Lu et al. Table 1
Efficacy of PDT in the treatment of various types of skin tumors.
Total number of cases Number of cases with recurrence in 6 months Number of cases with recurrence in 1 year
BCC
Bowen’s disease
Paget’s disease
SCC
32 0
13 0
8 0
5 0
0
0
5
2
Discussion With the aging of Chinese population, environmental pollution, lifestyle changes and China’s huge population base, the incidence of skin cancer is getting higher and higher. Skin cancer often occurs at the surface, which may result in the disfigurement due to the rapid growth of the tumor and the shift or destruction of the body surface organs. The skin cancer patients are currently not only looking for the extension of life but also the recovery of normal appearance and function. In the treatment of skin malignant tumors, prevention of local recurrence and functional reconstruction are two most important issues that must be simultaneously considered. These two issues (removal of tumor cells and maintenance of beauty and functions) are also contracted during the treatment of skin cancer, which requires the physicians to take comprehensive considerations based on the principles of cancer surgery, plastic surgery and skin surgery. Typical approach for the treatment of malignant tumors is the large areas of cancer resection. However, considering that skin malignant tumors, particularly nonmelanoma cancer, are located in the superficial position and their recurrence in the original places is more common than distant or regional lymph node metastasis, appropriate expansion of the resection is necessary. Therefore, we should not only emphasizes the expansion of the surgical area, but also consider the difficulties in the wound recovery if the surgical area is too large. Meanwhile, for the old patients, patients with tumors located in the head, face, perineum or patients with diabetes, hypertension and heart disease, extended surgery is limited by its poor effect on beauty, flap necrosis and difficulties in wound healing. PDT is a treatment option particularly well-suited for superficial (pre)malignant skin lesions due to the skin’s accessibility to light. ALA-PDT is a brand new therapeutic technology, which combines photosensitizer and corresponding light to selectively destroy the neoplastic lesions through photodynamic reactions. Its therapeutic efficacy in the treatment of skin tumors such as Bowen’s disease and other benign skin disease such as acne, verruca planae, genital warts and even skin photoaging has been widely recognized [4—8]. ALA, a precursor produced during the process of hemoglobin synthesis, is a recently developed second generation of photosensitizer. ALA can be selectively absorbed and accumulated by cells with active proliferations. The absorbed ALA is transformed into protoporphyrin IX (PpIX), and finally hemoglobin is synthesized [9,10]. Intracellular PpIX is a very strong photosensitive material, which produces photodynamic reactions after irradiation with special
wavelength light [9]. The produced reactive oxygen species, e.g., singlet oxygen, can selectively kill tumor cells and strong proliferative cells without significant effect on the surrounding normal cells [11—13]. Therefore, ALA is safe to normal cells compared to surgical excision, curettage surgery, freezing, laser, local chemotherapy and radiotherapy. Because of its good selectivity for tumors cells and suitability for skin medication, PDT does not impair the function of normal tissues and destroy normal cells. PDT does not produce apparent irritation and scarring. Pain is one of the major adverse effects during and after the treatment, especially in extensive lesion with multiple tumor [14,15]. However, Attili et al. analyzed the relationship between various parameters and pain during PDT and observed no association between pain and lesion diameter or pro-drug or dose or diagnosis [16]. In our study, mild to moderate pain was suffered during PDT. In addition, ALA has quick metabolic reactions without accumulation and resistance. Therefore, it is not limited by the number of the lesions and the skin location. ALA-PDT can be repeatedly utilized for recurrent patients without compromising the efficacy [17]. So in our study, the recurrence cases experienced another treatment of combination of surgery and PDT. Currently, some of the authoritative cancer treatment guidelines have listed PDT as one of the standard treatments for skin cancer [3], especially for nonmelanoma skin cancer like Bowen’s disease and basal cell carcinoma [7]. However, clinical experiences of PDT on the treatment of other epidemiological malignant tumors other than basal cell carcinoma and squamous cell carcinoma are still lacking. The perianal skin is a common area for extra-mammary Paget’s disease development. Wide excision of the lesions usually results in a large perianal tissue defect requiring a special operative technique for its coverage, especially for recurring perianal Paget’s disease [18]. Despite what appears to be adequate margins, recurrence rates are high because of the poor correlation between clinically evident disease compared with histologic findings, and the multifocal nature of extramammary Paget’s disease. In this study, surgical removal of visible lesions was followed by PDT, which could suppress the development of perianal Paget’s disease. In order to improve the efficacy of PDT in nonmelanoma skin cancer, the standard times and schemes of PDT for the treatment of various types of malignant skin tumor should be further investigated. In this study, the laser with a wavelength of 635 nm has a less than 6 mm of penetration depth in the skin tissues [19], which limited the downward penetration of
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Efficacy of topical ALA-PDT photosensitive reactions and inevitably influenced the therapeutic depth. Thus, it normally requires 3 sessions of PDT to achieve complete regression of the cancer. The high recurrence rate in extramammary Paget’s disease, can also due to the limitation of laser penetration in the tumor. In these cases, the visible lesions (1 mm beyond the edge) were completely removed in 40 cases. In order to decrease the rate of recurrence, we adopted PDT to kill the residual tumor cells. Another 18 cases had a unique position of tumor growth (located in the inner canthus, scrotum and penis). Therefore, surgery can only remove the obvious lesions or the lesions with significant proliferations. The remaining residual tumor tissue was eliminated by PDT one week after the surgery. Our results showed that complete or partial removal of the lesions provided a smooth path for the laser penetration, which relatively increased the treatment depth and reduced the treatment time. The lesion was completely subsided after 3 times of PDT. In summary, as an assisted therapeutic approach of skin tumor resection, PDT can reduce the excision range of the tumor lesion with well cosmetic results. Moreover, PDT can play a significant role in the combination treatment of tumors (especially head, facial and genital lesions) which are extremely difficult to be removed completely by surgical excision. However, its role in the reduction of recurrence rate needs to be further explored [10,20]. In addition, with the development and refinement of more optimal therapeutic agents and illumination devices, oncologic PDT will play more important role in the treatment of malignant skin tumors [21].
Conflicts of interest The authors have no conflict of interest to report.
Acknowledgment This work was supported by the National Natural Science Foundation of China (No. 81172211).
References [1] Rubin AI, Chen EH, Ratner D. Basal cell carcinoma. N Engl J Med 2005;353:2262—9. [2] Braathen LR, Szeimies RM, Basset-Seguin N, Bissonnette R, Foley P, Pariser D, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol 2007;56:125—43. [3] Gold MH, Goldman MP. 5-Aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg 2004;30:1083—4.
5 [4] Lu YG, Wu JJ, He Y, Yang HZ, Yang YD, et al. Efficacy of topical aminolevulinic acid photodynamic therapy for the treatment of verruca planae. Photomed Laser Surg 2010;28:561—3. [5] Choudhary S, Nouri K, Elsaie ML. Photodynamic therapy in dermatology: a review. Lasers Med Sci 2009;24:971—80. [6] Hu A, Moore C, Yu E, Mount G, Jordan K, Vujovic O, et al. Evaluation of patient-perceived satisfaction with photodynamic therapy for Bowen disease. J Otolaryngol Head Neck Surg 2010;39:688—96. [7] Sidoroff A, Thaler P. Taking treatment decisions in nonmelanoma skin cancer — the place for topical photodynamic therapy (PDT). Photodiagn Photodyn Ther 2010;7:24—32. [8] Kohl E, Karrer S. Photodynamic therapy for photorejuvenation and non-oncologic indications: overview and update. G Ital Dermatol Venereol 2011;146:473—85. [9] Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, et al. Guidelines for topical photodynamic therapy report of a workshop of the British Photodermatology Group. Br J Dermatol 2002;146:552—67. [10] Dögnitz N, Salomon D, Zellweger M, Ballini JP, Gabrecht T, Lange N, et al. Comparison of ALA- and ALA hexyl-esterinduced PpIX depth distribution in human skin carcinoma. J Photochem Photobiol B 2008;93:140—8. [11] Hillemanns P, Untch M, Dannecker C, Baumgartner R, Stepp H, Diebold J, et al. Photodynamic therapy of vulvar intraepithelial neoplasia using 5-aminolevulinic acid. Int J Cancer 2000;85:649—53. [12] Piette J, Volanti C, Vantieghem A, Matroule JY, Habraken Y, Agostinis P. Cell death and growth arrest in response to photodynamic therapy with membrane-bound photosensitizers. Biochem Pharmacol 2003;66:1651—9. [13] Wu RW, Yow CM, Wong CK, Lam YH. Photodynamic therapy (PDT) — initiation of apoptosis via activation of stress-activated p38 MAPK and JNK signal pathway in H460 cell lines. Photodiagn Photodyn Ther 2011;8:254—63. [14] Gholam P, Denk K, Sehr T, Enk A, Hartmann M. Factors influencing pain intensity during topical photodynamic therapy of complete cosmetic units for actinic keratoses. J Am Acad Dermatol 2010;63:213—8. [15] Tyrrell J, Campbell SM, Curnow A. The effect of air cooling pain relief on protoporphyrin IX photobleaching and clinical efficacy during dermatological photodynamic therapy. J Photochem Photobiol B 2011;103:1—7. [16] Attili SK, Dawe R, Ibbotson SA. Review of pain experienced during topical photodynamic therapy — our experience in Dundee. Photodiagn Photodyn Ther 2011;8:53—7. [17] Morton CA. Photodynamic therapy for nonmelanoma skin cancer and more. Arch Dermatol 2004;140:116—20. [18] Kyriazanos ID, Stamos NP, Miliadis L, Noussis G, Stoidis CN. Extra-mammary Paget’s disease of the perianal region: a review of the literature emphasizing the operative management technique. Surg Oncol 2011;20:e61—71. [19] Nootheti. PK, Goldman MP. Aminolevulinic acid-photodynamic therapy for photorejuvenation. Dermatol Clin 2007;25:35—45. [20] Allison RR, Bagnato VS, Sibata CH. Future of oncologic photodynamic therapy. Future Oncol 2010;6:929—40. [21] Lee Y, Baron ED. Photodynamic therapy: current evidence and applications in dermatology. Semin Cutan Med Surg 2011;30:199—209.
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Photodiagnosis and Photodynamic Therapy (2014) xxx, xxx—xxx
Available online at www.sciencedirect.com
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Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor Yuan-gang Lu MD, Ph.D. ∗, Yuan-yuan Wang 1, Ya-dong Yang 1, Xing-cun Zhang 1, Yang Gao 2, Yang Yang 2, Jun-bo Zhang 2, Guo-ling Li 2 Department of Plastic & Cosmetic Surgery, Research Institute of Surgery, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Daping, Chongqing 400042, PR China
KEYWORDS Topical photodynamic therapy; Aminolevulinic acid; Skin malignant tumor; Surgery
Summary Background: Photodynamic therapy (PDT) is a successful treatment for non-melanoma skin cancers in clinical practice. In China, more and more doctors use PDT to cure the patients with skin cancer, especially in the elder. The purpose of this study was to evaluate the efficacy of topical PDT using aminolevulinic acid (5-ALA) combined with excision in the treatment of skin malignant tumor and its role in surgical improvements. Methods: A total of 58 cases including 32 cases of BCC, 13 cases of Bowen’s disease, 8 cases of Paget’s disease and 5 cases of SCC were included in this study. All cases were treated with topical ALA-PDT after surgery. Each tumor region was irradiated with 120 J/cm2 using a 635-nm laser for 15 min. A total of 3 times of assisted ALA-PDT was applied after surgery. Results: There was no recurrence in 6 months after treatment. Only 5 cases of Paget’s disease and 2 cases of SCC experienced disease recurrence in 1 year. All patients were able to complete the treatment protocol, with well cosmetic results and no moderate adverse reactions. Conclusions: As an assistive therapy after tumor resection, ALA-PDT can reduce the excision range of the tumor lesions. However, its role in the reduction of recurrence rate remains to be further investigated. © 2014 Elsevier B.V. All rights reserved.
∗
Corresponding author. Tel.: +86 23 68757597; fax: +86 23 68757596. E-mail addresses: [email protected] (Y.-g. Lu), [email protected] (Y.-y. Wang), [email protected] (Y.-d. Yang), [email protected] (X.-c. Zhang), [email protected] (Y. Gao), [email protected] (Y. Yang), [email protected] (J.-b. Zhang), [email protected] (G.-l. Li). 1 Tel.: +86 23 68757597; fax: +86 23 68757596. 2 Tel: +86 23 68757590; fax: +86 23 68757596. http://dx.doi.org/10.1016/j.pdpdt.2014.02.006 1572-1000/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Introduction Skin cancer, particularly nonmelanoma skin tumor, frequently occurs in the exposed parts of the body, e.g., head, face, neck and arms. Invasive growth of the tumors results in the local tissue destruction, leading to the disfigurement due to the displacement of surface organs. Traditional surgery, freezing, radiation and chemotherapy have good therapeutic efficacy to the primary malignant tumor of the skin. However, they are traumatic and are prone to scar formation. In addition, these therapies have very limited effect in beauty [1]. With the economic and social development, the pursuit for good appearance becomes higher and higher. People are looking for the tumor therapies that have less recurrence rate, less pain, less side effects, and do not cause resistance after multiple treatments. How to meet the therapeutic requirement of patients with skin malignancies is one of the clinical challenges. Topical photodynamic therapy (PDT) is a treatment in which 5-ALA is distributed to the lesions and then a light source with specific wavelength enters the lesions to selectively destroy these lesions. As a novel therapy, PDT has good selectivity for tumor tissues, does not destroy normal cells and is not limited by the location or size of the skin lesions. In addition, PDT can be used for multiple times without resistance, and scar formation. Thus, PDT has been more and more applied in the treatment of nonmelanoma skin cancers, and even becomes one of the standard treatments [2,3]. Our department admitted a total of 58 cases with malignant skin tumors from January 2009 to December 2011. We used topical PDT combined with excision to treat these patients and reported the results below.
Patients and methods A total of 58 patients (male: 42; female: 16) were diagnosed as skin cancer from January 2009 to December 2011. These patients had an age of 45—81 years old and a disease course of 9 months to 6 years. Lesions were located in the face, the inner canthus, head and tempus, mouth, neck, limbs, abdomen, penis and vulva, etc. Single lesion occurred in 41 cases and multiple lesions occurred in 17 cases. Eighteen cases had a lesion of less than 2 cm in diameter, 25 cases had a lesion between 3 and 4 cm and 15 cases had a lesion of larger than 5 cm. Histological analysis confirmed that 32 cases had basal cell carcinoma, 13 cases had Bowen’s disease, 8 cases had Paget’s disease and 5 had squamous cell carcinoma. All cases had surgical resection of the lesions followed by ALA-PDT. Eighteen cases received ALAPDT after incomplete surgical resection because the cancer is extremely difficult to be cleaned. Patients with photosensitive history, serious system diseases or severe immune dysfunction or suppression were excluded from the study. Photosensitizer (5-ALA, Shanghai Fudan-Zhangjiang Biomedical Corporation, Shanghai, China) was dissolved in 5% Azone and 10% of 5-ALA emulsion was prepared before treatment. Light source was produced by XD-635AB photodynamic laser therapy instrument (Guilin XINGDA photoelectric Medical Devices Co., Ltd., Guilin, China) with an output wavelength of 635 nm, output power of 200 mW/cm2 and energy density of 120 J/cm2 . All patients
signed informed consent. The details of the surgery, PDT indications, treatment principles, efficacy, possible complications and precautions were explained to the patients before treatment. According to the tumor type, incisions were made along the lesion edge (1 mm beyond the margin). The lesions were completely removed in 40 cases from the subcutaneous fat layer, superficial or deep surface of the fascia to the periosteal surface. According to the size and depth of the wound site, we directly sutured or repaired the wound sites by transplanting appropriate flap or skin graft. For the malignant tumors in special positions, the lesions in 18 cases were removed as much as possible under the condition of maintaining key structures. ALA-PDT was performed 1 week after the surgery and a total of 3 times of PDT was applied. The interval between two treatments was two weeks. The treatment regions including operation area outside the edge of 2.0 cm, were infiltrated with azone for 30 min. Then, 10% topical ALA in an oil-in-water emulsion (5% azone) was applied to the skin of therapy area (2.0 cm beyond the visible lesions) for 4h incubation period under a light-shielding dressing. The target regions were irradiated by the laser with a wavelength of 635 nm, the output power of 200 mW/cm2 , light dose 120 J/cm2 and the exposure time of 15 min for each 3 cm2 field. The photosensitizer was freshly prepared with less than 4 h before therapy. After PDT, prednisone (20 mg/d), Ketotifen Fumarate (1 mg, BID) and cold wet dressings for 2 days were applied. Light was strictly avoided for 2 days after treatment. Scratching was avoided during the process of recovery. At 6 months or one year after termination of therapy, the efficacy of treatment and patient satisfaction, including lesion response and cosmetic effect, were investigated. Occurrence of new lesions in the receded areas was considered as recurrence. Patient satisfaction was graded as satisfaction, less satisfaction, and dissatisfaction.
Results In the group with combination of surgery and PDT, visible lesions were completed removed in 40 patients (Fig. 1a—c), while tumors were partially removed in 18 patients due to the special position (in the inner canthus, scrotum, penis, etc.). After three times of PDT, skin lesions were completely receded (Fig. 2a—d). There was no recurrence after 6 months of treatment. In the one-year follow-up, recurrence was observed in 5 cases of Paget’s disease, 2 cases of squamous cell carcinoma. Recurrence was not observed in other types of tumors. The overall one-year recurrence rate was 12.5% (Table 1). At one year after termination of therapy, all patients were satisfied with therapy effects. The recurrence cases received another surgical excision followed by PDT. Mild to moderate pain was commonly experienced during PDT. All patients have a mild local swelling, which was spontaneously receded after 1—2 days. Significant swelling was treated with cold compress. Swelling was lessened and its duration was shortened by follow-up therapies. Some patients had hyperpigmentation after the rash was subsided which faded within 1—2 weeks. No scar formation was found.
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Figure 1 (a) Left facial basal cell carcinoma. (b) Presentations after 5 days of tumor resection. (c) Presentations after 1 year of resection and PDT.
Figure 2 (a) Basal cell carcinoma in the right inner canthal before treatment. (b) Tumors involving the medial canthal tendon and adjacent lacrimal punctum. (c) Tumor resection and autologous transplantation of skin graft. (d) Presentations after 6 months of resection and PDT.
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Y.-g. Lu et al. Table 1
Efficacy of PDT in the treatment of various types of skin tumors.
Total number of cases Number of cases with recurrence in 6 months Number of cases with recurrence in 1 year
BCC
Bowen’s disease
Paget’s disease
SCC
32 0
13 0
8 0
5 0
0
0
5
2
Discussion With the aging of Chinese population, environmental pollution, lifestyle changes and China’s huge population base, the incidence of skin cancer is getting higher and higher. Skin cancer often occurs at the surface, which may result in the disfigurement due to the rapid growth of the tumor and the shift or destruction of the body surface organs. The skin cancer patients are currently not only looking for the extension of life but also the recovery of normal appearance and function. In the treatment of skin malignant tumors, prevention of local recurrence and functional reconstruction are two most important issues that must be simultaneously considered. These two issues (removal of tumor cells and maintenance of beauty and functions) are also contracted during the treatment of skin cancer, which requires the physicians to take comprehensive considerations based on the principles of cancer surgery, plastic surgery and skin surgery. Typical approach for the treatment of malignant tumors is the large areas of cancer resection. However, considering that skin malignant tumors, particularly nonmelanoma cancer, are located in the superficial position and their recurrence in the original places is more common than distant or regional lymph node metastasis, appropriate expansion of the resection is necessary. Therefore, we should not only emphasizes the expansion of the surgical area, but also consider the difficulties in the wound recovery if the surgical area is too large. Meanwhile, for the old patients, patients with tumors located in the head, face, perineum or patients with diabetes, hypertension and heart disease, extended surgery is limited by its poor effect on beauty, flap necrosis and difficulties in wound healing. PDT is a treatment option particularly well-suited for superficial (pre)malignant skin lesions due to the skin’s accessibility to light. ALA-PDT is a brand new therapeutic technology, which combines photosensitizer and corresponding light to selectively destroy the neoplastic lesions through photodynamic reactions. Its therapeutic efficacy in the treatment of skin tumors such as Bowen’s disease and other benign skin disease such as acne, verruca planae, genital warts and even skin photoaging has been widely recognized [4—8]. ALA, a precursor produced during the process of hemoglobin synthesis, is a recently developed second generation of photosensitizer. ALA can be selectively absorbed and accumulated by cells with active proliferations. The absorbed ALA is transformed into protoporphyrin IX (PpIX), and finally hemoglobin is synthesized [9,10]. Intracellular PpIX is a very strong photosensitive material, which produces photodynamic reactions after irradiation with special
wavelength light [9]. The produced reactive oxygen species, e.g., singlet oxygen, can selectively kill tumor cells and strong proliferative cells without significant effect on the surrounding normal cells [11—13]. Therefore, ALA is safe to normal cells compared to surgical excision, curettage surgery, freezing, laser, local chemotherapy and radiotherapy. Because of its good selectivity for tumors cells and suitability for skin medication, PDT does not impair the function of normal tissues and destroy normal cells. PDT does not produce apparent irritation and scarring. Pain is one of the major adverse effects during and after the treatment, especially in extensive lesion with multiple tumor [14,15]. However, Attili et al. analyzed the relationship between various parameters and pain during PDT and observed no association between pain and lesion diameter or pro-drug or dose or diagnosis [16]. In our study, mild to moderate pain was suffered during PDT. In addition, ALA has quick metabolic reactions without accumulation and resistance. Therefore, it is not limited by the number of the lesions and the skin location. ALA-PDT can be repeatedly utilized for recurrent patients without compromising the efficacy [17]. So in our study, the recurrence cases experienced another treatment of combination of surgery and PDT. Currently, some of the authoritative cancer treatment guidelines have listed PDT as one of the standard treatments for skin cancer [3], especially for nonmelanoma skin cancer like Bowen’s disease and basal cell carcinoma [7]. However, clinical experiences of PDT on the treatment of other epidemiological malignant tumors other than basal cell carcinoma and squamous cell carcinoma are still lacking. The perianal skin is a common area for extra-mammary Paget’s disease development. Wide excision of the lesions usually results in a large perianal tissue defect requiring a special operative technique for its coverage, especially for recurring perianal Paget’s disease [18]. Despite what appears to be adequate margins, recurrence rates are high because of the poor correlation between clinically evident disease compared with histologic findings, and the multifocal nature of extramammary Paget’s disease. In this study, surgical removal of visible lesions was followed by PDT, which could suppress the development of perianal Paget’s disease. In order to improve the efficacy of PDT in nonmelanoma skin cancer, the standard times and schemes of PDT for the treatment of various types of malignant skin tumor should be further investigated. In this study, the laser with a wavelength of 635 nm has a less than 6 mm of penetration depth in the skin tissues [19], which limited the downward penetration of
Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
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Efficacy of topical ALA-PDT photosensitive reactions and inevitably influenced the therapeutic depth. Thus, it normally requires 3 sessions of PDT to achieve complete regression of the cancer. The high recurrence rate in extramammary Paget’s disease, can also due to the limitation of laser penetration in the tumor. In these cases, the visible lesions (1 mm beyond the edge) were completely removed in 40 cases. In order to decrease the rate of recurrence, we adopted PDT to kill the residual tumor cells. Another 18 cases had a unique position of tumor growth (located in the inner canthus, scrotum and penis). Therefore, surgery can only remove the obvious lesions or the lesions with significant proliferations. The remaining residual tumor tissue was eliminated by PDT one week after the surgery. Our results showed that complete or partial removal of the lesions provided a smooth path for the laser penetration, which relatively increased the treatment depth and reduced the treatment time. The lesion was completely subsided after 3 times of PDT. In summary, as an assisted therapeutic approach of skin tumor resection, PDT can reduce the excision range of the tumor lesion with well cosmetic results. Moreover, PDT can play a significant role in the combination treatment of tumors (especially head, facial and genital lesions) which are extremely difficult to be removed completely by surgical excision. However, its role in the reduction of recurrence rate needs to be further explored [10,20]. In addition, with the development and refinement of more optimal therapeutic agents and illumination devices, oncologic PDT will play more important role in the treatment of malignant skin tumors [21].
Conflicts of interest The authors have no conflict of interest to report.
Acknowledgment This work was supported by the National Natural Science Foundation of China (No. 81172211).
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Please cite this article in press as: Lu Y-g, et al. Efficacy of topical ALA-PDT combined with excision in the treatment of skin malignant tumor. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.02.006
