- Email: [email protected]
Preliminary results of comparative study for subsequent photodynamic therapy versus secondary excision after primary excision for treating basal cell carcinoma
Accepted Manuscript Title: Preliminary results of comparative study for subsequent photodynamic therapy versus secondary excision after primary excision for treating basal cell carcinoma Author: Wenbo Bu Mengli Zhang Qian Zhang Chunyu Yuan Xu Chen Fang Fang PII: DOI: Reference:
S1572-1000(16)30138-7 http://dx.doi.org/doi:10.1016/j.pdpdt.2016.11.003 PDPDT 851
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
27-7-2016 24-10-2016 4-11-2016
Please cite this article as: Bu Wenbo, Zhang Mengli, Zhang Qian, Yuan Chunyu, Chen Xu, Fang Fang.Preliminary results of comparative study for subsequent photodynamic therapy versus secondary excision after primary excision for treating basal cell carcinoma.Photodiagnosis and Photodynamic Therapy http://dx.doi.org/10.1016/j.pdpdt.2016.11.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Revised manuscript PDPDT_2016_64
Preliminary results of comparative study for subsequent photodynamic therapy versus secondary excision after primary excision for treating basal cell carcinoma
Author names Wenbo Bu, Mengli Zhang, Qian Zhang, Chunyu Yuan, Xu Chen*, Fang Fang*
Affiliations Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, 210042, China Corresponding author: Xu Chen: [email protected] and Fang Fang: [email protected]
Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, 12 Jiangwangmiao St., Nanjing 210042, China Fax: +86 25 85414477 Running title: excision and photodynamic therapy in treatment of basal cell carcinoma Total word count: 927
Number of references: 4 Figures: 1 Table: 2
CONFLICT OF INTEREST The authors state no conflict of interest. ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (No. 81371755), the PhD Programs Foundation of Ministry of Education of China (20131106120046), the Jiangsu Provincial Special Program of Medical Science （ BL2012003) and the Jiangsu Province Natural Science Foundation (No. BK20131064). Wenbo Bu and Xu Chen are supported by the PUMC Youth Fund and Fundamental
Research
Funds
2016RC320005, 3332014008).
for
the
Central
Universities
(3332015116,
Bullet Points A few BCCs are indistinguishable from nevi based on clinical manifestations. The initial surgical treatment is failure to achieve radical removal under above situation. ALA-PDT sever as a considerable remedial treatment when nevi-like BCC underwent in situ resection.
Abstract Some basal cell carcinomas (BCCs) are indistinguishable from nevi based on clinical manifestations. Therefore, it is often difficult for the excision margins of the initial surgical treatment to achieve radical removal of the malignancy. This study was a
comparative
analysis
of
the
clinical
results
of
aminolevulinic
acid
(ALA)-photodynamic therapy (PDT) or secondary surgery after the primary excision. In total, 20 patients with preoperative clinical diagnoses of nevi underwent in situ resection. The postoperative pathological diagnoses confirmed all cases were BCC. Ten patients received PDT twice after the primary excision, and 10 cases received extended resection after the primary excision. Patients were followed up for 8 months at least, and the 2 groups did not show statistically significant differences in the recurrence rate, while the PDT group had better results in terms of economic burden, healing period, and cosmetic satisfaction than the group with secondary surgery. Our study demonstrates that ALA-PDT can sever as a considerable remedial treatment for the BCC patients who have not accepted radical resection due to primary clinical misdiagnosis. Keywords: Basal cell carcinoma; photodynamic therapy; excision
Short Communications Background Basal cell carcinoma (BCC) is the most common dermatological malignancy. A few BCCs are indistinguishable from nevi based on clinical manifestations. Surgery is the preferred BCC treatment. For BCCs that are indistinguishable from nevi, it is often difficult for the excision margins of the initial surgical treatment to achieve radical removal of the malignancy. Therefore, after pathological confirmation, secondary surgery or other adjuvant therapy should be performed to clear subclinical residual lesions. It has been confirmed that aminolevulinic acid (ALA)-photodynamic therapy (PDT) is an effective treatment for BCC [1].
Aims 20 cases of BCC patients who were initially diagnosed with nevi and received either ALA-PDT or secondary surgery after initial surgical resection in situ were enlisted in our study. We compared the tumor-free rate, economic burden, healing period, and cosmetic satisfaction between the 2 groups.
Methods General information We recorded the age, gender, location, course of disease, and lesion size of patients. Primary surgery Fusiform excision in situ was conducted along the visible boundary of skin lesions, with the depth reaching the fat layer. "Remedial" treatment after pathological feedback The choices of which remedial treatments were made according to the patients’ decision and informed consents had been signed. ALA-PDT Ten cases received PDT twice (once a week) at 7 days after the in-situ resection. A 20% 5-ALA hydrochloride (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., China) solution in saline was prepared. An area extending 0.5 cm beyond the
primary excision area in all directions was dressed with sterile cotton soaked with the above solution. After wrapping, the area was not exposed to light for 4 hours and then was irradiated at a 635-nm wavelength with a power density of 62.5 mW/cm2. The irradiation time was 20 min. Pathological examination was performed at 1 to 3 months after PDT. Secondary excision Ten cases received secondary excision 7 days after the primary surgery. The surgical resection area extended 0.5 cm beyond the original incision in all directions. After excision, a pathological examination was performed again, and the results all suggested the absence of residual tumor cells. Follow-up Follow-up for at least 8 months was conducted by combining outpatient visits with telephone inquiries. We recorded the rate of clinical relapses, overall cost, healing period, and cosmetic satisfaction. Statistical analysis Statistical analysis was performed using the chi-square test and Student’s t-test, and the significance level was P<0.05.
Results The 20 patients received treatment from the outpatient department in our hospital from April 2015 to January 2016. The patients included 12 males and 8 females, were aged 41-85 years, and had a disease duration from 4 months to 10 years. Sixteen patients had skin lesions located on the face, distributed on the forehead, eyebrow, eyelid, cheeks, and nose. There were 2 cases with skin lesions located on the shoulder, 1 case with skin lesions located on the neck, and 1 case with skin lesions located on the right thigh. The tumor size varied from the size of 0.4 to 1.5 cm2 (Table 1). In total, these patients with preoperative clinical diagnoses of nevi underwent in situ resection. The following pathological examination indicated the diagnosis of BCC (the types of BCC in 20 cases were mentioned in Table 1) and remaining tumor tissues in all 20 cases. Then, ten patients received PDT twice after the primary excision, and 10 cases
received extended resection after the primary excision. Patients were followed up for 8 months at least. The PDT group had better results in terms of cosmetic satisfaction. The details of representative cases from two groups were shown in Figure.1. Our research indicates that the 2 groups did not show statistically significant differences in the tumor-free rate (100% versus 100%), indicating that in situ resection combined with PDT can achieve the same effect as extended resection after primary excision. While the PDT group had better results in terms of economic burden (3450.00±158.11 RMB versus 4850.00±241.52 RMB), healing period (7.30±0.95 day versus 15.30±2.36 day) and cosmetic satisfaction (100% versus 30%) than did the group with secondary surgery (Table 2). Conclusion Souza et al. [2] reported the results of a 5-year follow-up of BCC patients who received ALA-PDT and did not undergo surgical resection. The tumor-free rate was 93.3% at 3 months after treatment, 81.8% at 12 months after treatment, 72.7% at 36 months after treatment, and 63.6% at 60 months after treatment. Therefore, they recommended using ALA-PDT as an adjuvant treatment after surgery. Roozeboom et al. [3] reported the therapeutic effect of ALA-PDT for treating nodular BCC. Before PDT, tumors were partially debulked by removing all tumor tissue above the skin level. After 60 months of follow-up, the ALA-PDT group had 23 cases of recurrence; however, only 2 cases of recurrence in surgical excision group. At the 3-month and 12-month follow-ups, the rates of treatment failure (including incomplete response or recurrent tumor) were 2/83, and 11/83, respectively. Therefore, they suggested that tumor thickness should be regarded when PDT was considered as treatment of nodular BCC. In fact, surgery combined with other forms of treatment has been reported in the treatment of BCC. For example, Thissen et al. [4] used topical imiquimod as the adjuvant therapy after Mohs surgery of large lesions or mixed BCC incomplete lesions. After 6 weeks of continuous topical application, there were no recurrent cases in 20-34 months of follow-up. In summary, our study demonstrates that ALA-PDT can sever as a considerable remedial treatment for the BCC patients who have not accepted radical resection due
to primary clinical misdiagnosis. The adequacy of ALA-PDT in this situation needs to be evaluated in a longer follow-up.
References [1]
S.H. Ibbotson, H. Moseley, L. Brancaleon, M. Padgett, M. O'Dwyer, J.A. Woods, A. Lesar, C. Goodman, J. Ferguson, Photodynamic therapy in dermatology: Dundee clinical and research experience, Photodiagnosis Photodyn. Ther. 1 (2004) 211-223.
[2]
C.S. Souza, L.B. Felicio, J. Ferreira, C. Kurachi, M.V. Bentley, A.C. Tedesco, V.S. Bagnato, Long-term follow-up of topical 5-aminolaevulinic acid photodynamic therapy diode laser single session for non-melanoma skin cancer, Photodiagnosis Photodyn. Ther. 6 (2009) 207-213.
[3]
M.H. Roozeboom, M.A. Aardoom, P.J. Nelemans, M.R. Thissen, N.W. Kelleners-Smeets, D.I. Kuijpers, K. Mosterd, Fractionated 5-aminolevulinic acid photodynamic therapy after partial debulking versus surgical excision for nodular basal cell carcinoma: a randomized controlled trial with at least 5-year follow-up, J. Am. Acad. Dermatol. 69 (2013) 280-287.
[4]
M.R. Thissen, D.I. Kuijpers, G.A. Krekels, Local immune modulator (imiquimod 5% cream) as adjuvant treatment after incomplete Mohs micrographic surgery for large, mixed type basal cell carcinoma: a report of 3 cases, J. Drugs Dermatol. 5 (2006) 461-464.
Figure legend Fig.1 The details of representative cases from two groups were shown respectively. We showed the clinical pictures before treatment, post primary excision, during "Remedial" treatment after pathological feedback and on follow up period respectively. The histological pictures after primary surgery and total treatment have also been exhibited respectively. The bars have been marked with the indicated length.
Tables
Table 1 General information of the all 20 cases of BCC patients Grouping
Gender
Age (X±S)
Course
Location
Size
of
Pathological type
disease M In
situ 5
resection
F 5
cases cases 57.50±9.65 （41-76）
plus PDT (10 cases)
6
9 cases on
0.4 cm2-
8 cases of
months
the face;
1.2 cm2
the nodular
-10
1 case on
type;
years
the neck
2 cases of the morphoeic type
In
situ 7
resection plus
3
4
cases cases 64.90±14.16 months （46-85）
7 cases on
0.4 cm2-
8 cases of
the face;
1.5 cm2
the nodular
-10
2 cases on
type;
years
the
2 cases of
excision
shoulder;
the
(10 cases)
1 case on
superficial
the
type
extended
thigh
right
Table 2 Follow-up table
Tumor-free rate
at
In situ removal
Extended
Statistical value
plus PDT
excision
100%
100%
2=0.000, p=1.000
3450.00±158.11
4850.00±241.52
T=5.684, p=0.028<0.05
7.30±0.95
15.30±2.36
T=-9.948, p=0.000<0.01
100%
30%
2=10.769, p=0.001<0.01
8
months
of
follow-up Total
cost
(RMB) Healing period (days) Cosmetic satisfaction
S1572-1000(16)30138-7 http://dx.doi.org/doi:10.1016/j.pdpdt.2016.11.003 PDPDT 851
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
27-7-2016 24-10-2016 4-11-2016
Please cite this article as: Bu Wenbo, Zhang Mengli, Zhang Qian, Yuan Chunyu, Chen Xu, Fang Fang.Preliminary results of comparative study for subsequent photodynamic therapy versus secondary excision after primary excision for treating basal cell carcinoma.Photodiagnosis and Photodynamic Therapy http://dx.doi.org/10.1016/j.pdpdt.2016.11.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Revised manuscript PDPDT_2016_64
Preliminary results of comparative study for subsequent photodynamic therapy versus secondary excision after primary excision for treating basal cell carcinoma
Author names Wenbo Bu, Mengli Zhang, Qian Zhang, Chunyu Yuan, Xu Chen*, Fang Fang*
Affiliations Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, 210042, China Corresponding author: Xu Chen: [email protected] and Fang Fang: [email protected]
Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, 12 Jiangwangmiao St., Nanjing 210042, China Fax: +86 25 85414477 Running title: excision and photodynamic therapy in treatment of basal cell carcinoma Total word count: 927
Number of references: 4 Figures: 1 Table: 2
CONFLICT OF INTEREST The authors state no conflict of interest. ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (No. 81371755), the PhD Programs Foundation of Ministry of Education of China (20131106120046), the Jiangsu Provincial Special Program of Medical Science （ BL2012003) and the Jiangsu Province Natural Science Foundation (No. BK20131064). Wenbo Bu and Xu Chen are supported by the PUMC Youth Fund and Fundamental
Research
Funds
2016RC320005, 3332014008).
for
the
Central
Universities
(3332015116,
Bullet Points A few BCCs are indistinguishable from nevi based on clinical manifestations. The initial surgical treatment is failure to achieve radical removal under above situation. ALA-PDT sever as a considerable remedial treatment when nevi-like BCC underwent in situ resection.
Abstract Some basal cell carcinomas (BCCs) are indistinguishable from nevi based on clinical manifestations. Therefore, it is often difficult for the excision margins of the initial surgical treatment to achieve radical removal of the malignancy. This study was a
comparative
analysis
of
the
clinical
results
of
aminolevulinic
acid
(ALA)-photodynamic therapy (PDT) or secondary surgery after the primary excision. In total, 20 patients with preoperative clinical diagnoses of nevi underwent in situ resection. The postoperative pathological diagnoses confirmed all cases were BCC. Ten patients received PDT twice after the primary excision, and 10 cases received extended resection after the primary excision. Patients were followed up for 8 months at least, and the 2 groups did not show statistically significant differences in the recurrence rate, while the PDT group had better results in terms of economic burden, healing period, and cosmetic satisfaction than the group with secondary surgery. Our study demonstrates that ALA-PDT can sever as a considerable remedial treatment for the BCC patients who have not accepted radical resection due to primary clinical misdiagnosis. Keywords: Basal cell carcinoma; photodynamic therapy; excision
Short Communications Background Basal cell carcinoma (BCC) is the most common dermatological malignancy. A few BCCs are indistinguishable from nevi based on clinical manifestations. Surgery is the preferred BCC treatment. For BCCs that are indistinguishable from nevi, it is often difficult for the excision margins of the initial surgical treatment to achieve radical removal of the malignancy. Therefore, after pathological confirmation, secondary surgery or other adjuvant therapy should be performed to clear subclinical residual lesions. It has been confirmed that aminolevulinic acid (ALA)-photodynamic therapy (PDT) is an effective treatment for BCC [1].
Aims 20 cases of BCC patients who were initially diagnosed with nevi and received either ALA-PDT or secondary surgery after initial surgical resection in situ were enlisted in our study. We compared the tumor-free rate, economic burden, healing period, and cosmetic satisfaction between the 2 groups.
Methods General information We recorded the age, gender, location, course of disease, and lesion size of patients. Primary surgery Fusiform excision in situ was conducted along the visible boundary of skin lesions, with the depth reaching the fat layer. "Remedial" treatment after pathological feedback The choices of which remedial treatments were made according to the patients’ decision and informed consents had been signed. ALA-PDT Ten cases received PDT twice (once a week) at 7 days after the in-situ resection. A 20% 5-ALA hydrochloride (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., China) solution in saline was prepared. An area extending 0.5 cm beyond the
primary excision area in all directions was dressed with sterile cotton soaked with the above solution. After wrapping, the area was not exposed to light for 4 hours and then was irradiated at a 635-nm wavelength with a power density of 62.5 mW/cm2. The irradiation time was 20 min. Pathological examination was performed at 1 to 3 months after PDT. Secondary excision Ten cases received secondary excision 7 days after the primary surgery. The surgical resection area extended 0.5 cm beyond the original incision in all directions. After excision, a pathological examination was performed again, and the results all suggested the absence of residual tumor cells. Follow-up Follow-up for at least 8 months was conducted by combining outpatient visits with telephone inquiries. We recorded the rate of clinical relapses, overall cost, healing period, and cosmetic satisfaction. Statistical analysis Statistical analysis was performed using the chi-square test and Student’s t-test, and the significance level was P<0.05.
Results The 20 patients received treatment from the outpatient department in our hospital from April 2015 to January 2016. The patients included 12 males and 8 females, were aged 41-85 years, and had a disease duration from 4 months to 10 years. Sixteen patients had skin lesions located on the face, distributed on the forehead, eyebrow, eyelid, cheeks, and nose. There were 2 cases with skin lesions located on the shoulder, 1 case with skin lesions located on the neck, and 1 case with skin lesions located on the right thigh. The tumor size varied from the size of 0.4 to 1.5 cm2 (Table 1). In total, these patients with preoperative clinical diagnoses of nevi underwent in situ resection. The following pathological examination indicated the diagnosis of BCC (the types of BCC in 20 cases were mentioned in Table 1) and remaining tumor tissues in all 20 cases. Then, ten patients received PDT twice after the primary excision, and 10 cases
received extended resection after the primary excision. Patients were followed up for 8 months at least. The PDT group had better results in terms of cosmetic satisfaction. The details of representative cases from two groups were shown in Figure.1. Our research indicates that the 2 groups did not show statistically significant differences in the tumor-free rate (100% versus 100%), indicating that in situ resection combined with PDT can achieve the same effect as extended resection after primary excision. While the PDT group had better results in terms of economic burden (3450.00±158.11 RMB versus 4850.00±241.52 RMB), healing period (7.30±0.95 day versus 15.30±2.36 day) and cosmetic satisfaction (100% versus 30%) than did the group with secondary surgery (Table 2). Conclusion Souza et al. [2] reported the results of a 5-year follow-up of BCC patients who received ALA-PDT and did not undergo surgical resection. The tumor-free rate was 93.3% at 3 months after treatment, 81.8% at 12 months after treatment, 72.7% at 36 months after treatment, and 63.6% at 60 months after treatment. Therefore, they recommended using ALA-PDT as an adjuvant treatment after surgery. Roozeboom et al. [3] reported the therapeutic effect of ALA-PDT for treating nodular BCC. Before PDT, tumors were partially debulked by removing all tumor tissue above the skin level. After 60 months of follow-up, the ALA-PDT group had 23 cases of recurrence; however, only 2 cases of recurrence in surgical excision group. At the 3-month and 12-month follow-ups, the rates of treatment failure (including incomplete response or recurrent tumor) were 2/83, and 11/83, respectively. Therefore, they suggested that tumor thickness should be regarded when PDT was considered as treatment of nodular BCC. In fact, surgery combined with other forms of treatment has been reported in the treatment of BCC. For example, Thissen et al. [4] used topical imiquimod as the adjuvant therapy after Mohs surgery of large lesions or mixed BCC incomplete lesions. After 6 weeks of continuous topical application, there were no recurrent cases in 20-34 months of follow-up. In summary, our study demonstrates that ALA-PDT can sever as a considerable remedial treatment for the BCC patients who have not accepted radical resection due
to primary clinical misdiagnosis. The adequacy of ALA-PDT in this situation needs to be evaluated in a longer follow-up.
References [1]
S.H. Ibbotson, H. Moseley, L. Brancaleon, M. Padgett, M. O'Dwyer, J.A. Woods, A. Lesar, C. Goodman, J. Ferguson, Photodynamic therapy in dermatology: Dundee clinical and research experience, Photodiagnosis Photodyn. Ther. 1 (2004) 211-223.
[2]
C.S. Souza, L.B. Felicio, J. Ferreira, C. Kurachi, M.V. Bentley, A.C. Tedesco, V.S. Bagnato, Long-term follow-up of topical 5-aminolaevulinic acid photodynamic therapy diode laser single session for non-melanoma skin cancer, Photodiagnosis Photodyn. Ther. 6 (2009) 207-213.
[3]
M.H. Roozeboom, M.A. Aardoom, P.J. Nelemans, M.R. Thissen, N.W. Kelleners-Smeets, D.I. Kuijpers, K. Mosterd, Fractionated 5-aminolevulinic acid photodynamic therapy after partial debulking versus surgical excision for nodular basal cell carcinoma: a randomized controlled trial with at least 5-year follow-up, J. Am. Acad. Dermatol. 69 (2013) 280-287.
[4]
M.R. Thissen, D.I. Kuijpers, G.A. Krekels, Local immune modulator (imiquimod 5% cream) as adjuvant treatment after incomplete Mohs micrographic surgery for large, mixed type basal cell carcinoma: a report of 3 cases, J. Drugs Dermatol. 5 (2006) 461-464.
Figure legend Fig.1 The details of representative cases from two groups were shown respectively. We showed the clinical pictures before treatment, post primary excision, during "Remedial" treatment after pathological feedback and on follow up period respectively. The histological pictures after primary surgery and total treatment have also been exhibited respectively. The bars have been marked with the indicated length.
Tables
Table 1 General information of the all 20 cases of BCC patients Grouping
Gender
Age (X±S)
Course
Location
Size
of
Pathological type
disease M In
situ 5
resection
F 5
cases cases 57.50±9.65 （41-76）
plus PDT (10 cases)
6
9 cases on
0.4 cm2-
8 cases of
months
the face;
1.2 cm2
the nodular
-10
1 case on
type;
years
the neck
2 cases of the morphoeic type
In
situ 7
resection plus
3
4
cases cases 64.90±14.16 months （46-85）
7 cases on
0.4 cm2-
8 cases of
the face;
1.5 cm2
the nodular
-10
2 cases on
type;
years
the
2 cases of
excision
shoulder;
the
(10 cases)
1 case on
superficial
the
type
extended
thigh
right
Table 2 Follow-up table
Tumor-free rate
at
In situ removal
Extended
Statistical value
plus PDT
excision
100%
100%
2=0.000, p=1.000
3450.00±158.11
4850.00±241.52
T=5.684, p=0.028<0.05
7.30±0.95
15.30±2.36
T=-9.948, p=0.000<0.01
100%
30%
2=10.769, p=0.001<0.01
8
months
of
follow-up Total
cost
(RMB) Healing period (days) Cosmetic satisfaction