Int J Clin Oncol DOI 10.1007/s10147-014-0686-2
ORIGINAL ARTICLE
Combination chemotherapy of low-dose 5-fluorouracil and cisplatin for advanced extramammary Paget’s disease Yasutaka Tokuda • Fuyuko Arakura Hisashi Uhara
•
Received: 17 January 2014 / Accepted: 9 March 2014 Ó Japan Society of Clinical Oncology 2014
Abstract Background Extramammary Paget’s disease (EPD) is a cutaneous adenocarcinoma. It is usually curable by wide local excision. However, the prognosis for EPD patients with metastases is extremely poor because effective chemotherapy for advanced EPD has not been established. Methods We retrospectively analyzed the efficacy of combination chemotherapy consisting of infusions of 5-fluorouracil (5-FU, 600 mg/m2/body, 5 days/week) and cisplatin (5–10 mg/body, 5–7 days/week) administered intravenously for 8–24 h (low-dose FP). Results The patients were 15 males and 7 females and the ages ranged from 54 to 91 years old (median 71). The toxicities of low-dose FP were as follows: hematopoietic dysfunction (n = 4), gastrointestinal dysfunction (4), nephropathy (1), and phlebitis (1). Almost all toxicities were grade 1 or 2 except for 2 cases with grade 3 leukopenia or pancytopenia. Seventeen patients were treated with low-dose FP only, and the clinical results included 10 partial responses (PR), 4 stable disease (SD), and 3 progressive disease (PD). The overall survival ranges (medians) were 5–51 months (12) in all 22 patients, 6–51 months (13) in the 13 patients showing complete response or PR, and 5–12 months (11) in the 6 SD patients. The reported palliative effects of low-dose FP include control of pain and improvement of lymphedema. Conclusion Although the number of cases is limited and there is a bias because cases without clinical effects are less Y. Tokuda F. Arakura Division of Dermatology, Matsumoto Medical Center, Minami, 2-20-30, Murai, Matsumoto, Nagano 399-8701, Japan H. Uhara (&) Department of Dermatology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan e-mail: [email protected]
likely to be reported, this regimen might be considered a relatively effective option for advanced EPD. Keywords Extramammary Paget’s disease Chemotherapy 5-Fluorouracil Cisplatin
Introduction Extramammary Paget’s disease (EPD) is a cutaneous adenocarcinoma, frequently occurring in the genital area. Although this disease is usually curable by wide local excision, the prognosis of patients with metastases is extremely poor. One reason is that the age of the majority of patients rules out intensive chemotherapy due to their organ fragility, and another is that an effective chemotherapy for advanced EPD has not been established yet. In 1997, we reported 3 cases of advanced EPD showing partial response (PR) without severe toxicity using the combination therapy of low-dose 5-fluorouracil (5-FU) and cisplatin (low-dose FP) therapy [1]. To date, this regimen has been mainly restricted to Japan. Moreover, the clinical effects have not been fully evaluated because the disease is rare and almost all cases have been reported as case reports. To evaluate the efficacy of this regimen, we reviewed the literature of cases treated with low-dose FP for advanced EPD.
Patients and methods Data collection All cases were gathered by MEDLINE or Japan Medical Abstracts Society (JAMAS) search. The collected data
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Int J Clin Oncol
were analyzed for the following factors: age, sex, clinical response and the duration, survival time, and toxicity. If the published data were insufficient, we obtained the details directly from the authors by telephone or e-mail. Therapy regimen Low-dose FP therapy consists of infusions of 5-FU (600 mg/m2/body, 5 days/week) and cisplatin (5–10 mg/ body, 5–7 days/week) administered intravenously for 8–24 h [1].
Results We found 18 articles that discussed 22 patients with advanced EPD treated with low-dose FP [1–18]. Table 1 summarizes the patient profiles. All patients were Japanese;
15 were male and 7 were female; and the age range was 54 to 91 years old (median 71). The overall response rate (RR) in the 22 cases was 59.0 %. Seventeen patients were treated with low-dose FP only, and the clinical response was 10 partial response (PR), 4 stable disease (SD), and 3 progressive disease (PD) (RR 58.8 %). The remaining 5 patients received both low-dose FP and radiation therapy: for them, the RR was 60 % [1 complete response (CR), 2 PR, 2 SD]. The duration (median) of CR, PR and SD was 24 months (24), 2–18 months (6) and 1.5–5 months (3), respectively. The overall survival (median) was 5–51 months (12) in all 22 patients, 6–51 months (13) in the 13 patients showing CR or PR, and 5–12 months (11) in the 6 SD patients. Two of 3 patients showing PD had received other chemotherapy before the low-dose FP. The toxicities of low-dose FP were as follows: hematopoietic dysfunction (n = 4), gastrointestinal dysfunction (4, including 1 each abdominal pain, anorexia, diarrhea,
Table 1 Cases Case no.
Age (years)
Sex
Clinical response
Duration of response (months)
Survival time (months)
Combination therapy
Toxicity
References
1 2
57 56
M M
PR PR
5 6
12 6
– –
– –
[1] [1]
3
74
M
PR
6
18
–
–
[1]
4
82
M
SD
2
8
–
Nephropathy
[2]
5
91
F
SD
2
11
–
Pancytopenia
[2]
6
82
F
PD
–
12
–
–
[2]
7
72
M
PR
4
7
–
–
[3]
8
54
M
PD
–
24?
–
–
[4]
9
64
M
SD
5
12
–
Abdominal pain
[5]
10
84
F
PR
10
20
–
–
[6]
11
64
M
SD
1.5
5
Radiation (before)
12
72
F
PR
5.3
51
–
13
82
M
PD
–
–
–
14
61
M
PR
14
16
Radiation
[7] G2 diarrhea, G3 leukopenia – G3 pancytopenia, G2 anorexia
[8] [9] [10]
15
78
F
PR
2
5
Radiation
–
[11]
16
70
F
SD
4
11
Radiation (before)
–
[12]
17
63
F
SD
4
12
–
G3 pancytopenia
[13]
18
67
M
PR
18
20
–
Mild phlebitis, mild nausea
[14]
19 20
72 64
M M
PR PR
6 13
10 13?
– –
– –
[15] [16]
21
73
M
PR
4
9
–
–
[17]
22
73
M
CR
24
40?
Radiation
–
[18]
CR complete response, PR partial response, SD stable disease, PD progressive disease
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Int J Clin Oncol
nausea), nephropathy (1), and phlebitis (1). Almost all toxicities were grade 1 or 2 except for 2 cases with grade 3 leukopenia or pancytopenia.
Although there are limitations to this review because cases without clinical effects are less likely to be reported, this regimen might be considered a relatively effective option for advanced EPD.
Discussion
Acknowledgments This study was supported in part by a National Cancer Center Research and Development Fund (23-A-22).
Extramammary Paget’s disease is a rare skin cancer generally affecting the genital region. Because the disorder is usually diagnosed as carcinoma in situ, the prognosis is generally favorable. However, the prognosis of patients with lymph node metastasis is extremely poor. Hatta et al. [19] reported that visceral metastasis occurred in 13 of 76 patients (17 %), and that 10 of these 13 patients (77 %) died of the disease. Despite the poor prognosis, the availability of systemic chemotherapy for advanced EPD has been limited. In 1990, Yokoyama et al. [20] reported a case of effective neoadjuvant chemotherapy consisting of mitomycin C, vincristine, and cisplatin. In 1992, Yamazaki et al. [21] reported combination chemotherapy consisting of 5-FU, epirubicin, carboplatin, vincristine, and mitomycin C, for which the clinical response was 3 PR and 5 SD (RR 37.5 %). Although the clinical effect of docetaxel has been reported, the number of examined cases is scant [22]. Two-thirds of the reported cases had shown some kind of clinical response. However this result could be higher than the actual value because cases without clinical effects are less likely to be reported. In the data from our hospital, 7 patients were treated and 3 PR (RR 43 %) were observed [2]. This review shows that there might be an association between clinical response and duration. The median duration of response with low-dose FP was 24 and 6 months in CR and PR patients, respectively, and longer than 3 months in SD patients. Furthermore, the median overall survival was 13 months in 13 patients showing CR or PR and longer than 11 months in SD patients. Because the toxicity of low-dose FP is relatively mild, this regimen hardly affected the quality of life even in older patients. Furthermore, palliative effects of low-dose FP have been reported. Otani et al. [8] reported that one patient showing PR had lived for over 4 years without hospitalization. Matsuura et al. [5] commented that lowdose FP could control pain and exudates from lesions. Ishizawa et al. [11] reported that this regimen was effective for carcinomatous lymphangiosis. Even in the cases showing SD, some authors stated that low-dose FP helped to maintain the patient’s quality of life and could contribute to the long-term survival with relief of symptoms. Because 2 of 3 patients showing PD had received other prior chemotherapy, low-dose FP may not work as second-line therapy [23].
Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Tokuda Y, Oguchi S, Yamazaki Y et al (1997) Low dose FP (5FU ? low-dose CDDP) therapy for advanced extramammary Paget’s disease. Jpn J Dermatol 107:21–27 (in Japanese) 2. Uhara H, Saida T (2003) Chemotherapy and immunotherapy for extramammary Paget’s disease and sweat gland carcinoma. Skin Cancer 18:92–98 (in Japanese) 3. Morita R, Kinbara T, Hatta N et al (1999) Low-dose FP therapy response in advanced extramammary Paget’s disease: a case report. Rinsyo Derma 41:1475–1477 (in Japanese) 4. Oguchi S, Kaneko M, Uhara H et al (2002) Docetaxel induced durable response in advanced extramammary Paget’s disease: a case report. J Dermatol 29:33–37 5. Mastuura A, Katakami C, Okuda F et al (2002) A case of extramammary Paget’s carcinoma with large tumor. Skin Cancer 17:189–192 (in Japanese) 6. Onishi I, Kamata T, Hayashi H et al (2002) A case of vulvar extramammary Paget’s disease associated with pancreatic cancer that was successfully treated with chemotherapy. Jpn Cancer Chemother 29:1973–1976 (in Japanese) 7. Uemura M, Mukai M, Fukuhara S et al (2002) A case of extramammary Paget’s disease with anuria. Acta Urol Jpn 48:311–314 (in Japanese) 8. Otani T, Endo S, Kato H et al (2003) A case of extramammary Paget’s carcinoma showing responsive to biochemical modulation chemotherapy. J Tokyo Women Med Univ 73:99–104 9. Inui S, Fukuhara S, Asada H et al (2000) Double involvement of extramammary Paget’s disease in genitalia and axilla. J Dermatol 27:409–412 10. Osawa R, Aoyagi S, Sawamura D et al (2005) A case of advanced extrramammary Paget’s carcinoma treated with low-dose FP (5FU ? CDDP) therapy and simultaneous radiotherapy. Skin Cancer 20:79–82 (in Japanese) 11. Ishizawa T, Konno T (2002) A case of extramammary Paget’s carcinoma whose chief complaint was reddening swelling on the left leg. Skin Cancer 17:234–237 (in Japanese) 12. Yokouchi M, Kobayashi M, Inazumi T (2007) A case of advanced axillary Paget’s disease. Rinsyo Hifuka 61:554–557 (in Japanese) 13. Kikuchi Y, Akita M, Kato S et al (2004) A case of advanced extramammary Paget’s disease treated with low-dose FP and internal PDT therapy. Jpn J Dermatol 114:1443 (in Japanese) 14. Kariya K, Tsuji T, Schwartz RA (2004) Trial of low-dose 5-fluorouracil/cisplatin therapy for advanced extramammary Paget’s disease. Dermatol Surg 30:341–344 15. Harasima T, Sinokawa Y, Himi Y (2007) The experience of treatment of recurrence extramammary Paget’s disease by lowdose FP therapy. J Jpn P R S 27:535 (in Japanese) 16. Shibuya Y, Arakawa C, Suzuki S et al (2008) Low-dose FP: an effective treatment of advanced extramammary Paget’s disease. Skin Cancer 23:375–378 (in Japanese)
123
Int J Clin Oncol 17. Yamamoto A, Yoneyama K, Ono S et al (2010) A case of secondary extramammary Paget’s disease. Tokyo J Obstet Gynecol 59:78–82 (in Japanese) 18. Yamada N, Kusakabe S, Tukamoto K et al (2010) Three cases of advanced extramammary Paget’s disease treated by chemo–radio therapy. Jpn J Dermatol 120:728 (in Japanese) 19. Hatta N, Yamada T, Hirono T et al (2008) Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol 158:313–318 20. Yokoyama Y, Mabuchi M, Kawabata I et al (1990) Metastatic vulvar Paget’s disease responding to combination chemotherapy. Jpn J Clin Oncol 20:426–430
123
21. Yamazaki N, Yamamoto A, Wada T et al (1999) A case of metastatic extramammary Paget’s disease that responded to combination chemotherapy. J Dermatol 26:311–316 22. Kurooka S, Namikawa K, Tsutsumida A et al (2012) A statistical study of 101 patients with extramammary Paget’s disease. Jpn J Dermatol 122:2891–2897 (in Japanese) 23. Mkoshiba Y, Uhara H, Kubo H et al (2013) S-1 induced a durable response in metastatic extramammary Paget’s disease. J Dermatol 40:664–665
ORIGINAL ARTICLE
Combination chemotherapy of low-dose 5-fluorouracil and cisplatin for advanced extramammary Paget’s disease Yasutaka Tokuda • Fuyuko Arakura Hisashi Uhara
•
Received: 17 January 2014 / Accepted: 9 March 2014 Ó Japan Society of Clinical Oncology 2014
Abstract Background Extramammary Paget’s disease (EPD) is a cutaneous adenocarcinoma. It is usually curable by wide local excision. However, the prognosis for EPD patients with metastases is extremely poor because effective chemotherapy for advanced EPD has not been established. Methods We retrospectively analyzed the efficacy of combination chemotherapy consisting of infusions of 5-fluorouracil (5-FU, 600 mg/m2/body, 5 days/week) and cisplatin (5–10 mg/body, 5–7 days/week) administered intravenously for 8–24 h (low-dose FP). Results The patients were 15 males and 7 females and the ages ranged from 54 to 91 years old (median 71). The toxicities of low-dose FP were as follows: hematopoietic dysfunction (n = 4), gastrointestinal dysfunction (4), nephropathy (1), and phlebitis (1). Almost all toxicities were grade 1 or 2 except for 2 cases with grade 3 leukopenia or pancytopenia. Seventeen patients were treated with low-dose FP only, and the clinical results included 10 partial responses (PR), 4 stable disease (SD), and 3 progressive disease (PD). The overall survival ranges (medians) were 5–51 months (12) in all 22 patients, 6–51 months (13) in the 13 patients showing complete response or PR, and 5–12 months (11) in the 6 SD patients. The reported palliative effects of low-dose FP include control of pain and improvement of lymphedema. Conclusion Although the number of cases is limited and there is a bias because cases without clinical effects are less Y. Tokuda F. Arakura Division of Dermatology, Matsumoto Medical Center, Minami, 2-20-30, Murai, Matsumoto, Nagano 399-8701, Japan H. Uhara (&) Department of Dermatology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan e-mail: [email protected]
likely to be reported, this regimen might be considered a relatively effective option for advanced EPD. Keywords Extramammary Paget’s disease Chemotherapy 5-Fluorouracil Cisplatin
Introduction Extramammary Paget’s disease (EPD) is a cutaneous adenocarcinoma, frequently occurring in the genital area. Although this disease is usually curable by wide local excision, the prognosis of patients with metastases is extremely poor. One reason is that the age of the majority of patients rules out intensive chemotherapy due to their organ fragility, and another is that an effective chemotherapy for advanced EPD has not been established yet. In 1997, we reported 3 cases of advanced EPD showing partial response (PR) without severe toxicity using the combination therapy of low-dose 5-fluorouracil (5-FU) and cisplatin (low-dose FP) therapy [1]. To date, this regimen has been mainly restricted to Japan. Moreover, the clinical effects have not been fully evaluated because the disease is rare and almost all cases have been reported as case reports. To evaluate the efficacy of this regimen, we reviewed the literature of cases treated with low-dose FP for advanced EPD.
Patients and methods Data collection All cases were gathered by MEDLINE or Japan Medical Abstracts Society (JAMAS) search. The collected data
123
Int J Clin Oncol
were analyzed for the following factors: age, sex, clinical response and the duration, survival time, and toxicity. If the published data were insufficient, we obtained the details directly from the authors by telephone or e-mail. Therapy regimen Low-dose FP therapy consists of infusions of 5-FU (600 mg/m2/body, 5 days/week) and cisplatin (5–10 mg/ body, 5–7 days/week) administered intravenously for 8–24 h [1].
Results We found 18 articles that discussed 22 patients with advanced EPD treated with low-dose FP [1–18]. Table 1 summarizes the patient profiles. All patients were Japanese;
15 were male and 7 were female; and the age range was 54 to 91 years old (median 71). The overall response rate (RR) in the 22 cases was 59.0 %. Seventeen patients were treated with low-dose FP only, and the clinical response was 10 partial response (PR), 4 stable disease (SD), and 3 progressive disease (PD) (RR 58.8 %). The remaining 5 patients received both low-dose FP and radiation therapy: for them, the RR was 60 % [1 complete response (CR), 2 PR, 2 SD]. The duration (median) of CR, PR and SD was 24 months (24), 2–18 months (6) and 1.5–5 months (3), respectively. The overall survival (median) was 5–51 months (12) in all 22 patients, 6–51 months (13) in the 13 patients showing CR or PR, and 5–12 months (11) in the 6 SD patients. Two of 3 patients showing PD had received other chemotherapy before the low-dose FP. The toxicities of low-dose FP were as follows: hematopoietic dysfunction (n = 4), gastrointestinal dysfunction (4, including 1 each abdominal pain, anorexia, diarrhea,
Table 1 Cases Case no.
Age (years)
Sex
Clinical response
Duration of response (months)
Survival time (months)
Combination therapy
Toxicity
References
1 2
57 56
M M
PR PR
5 6
12 6
– –
– –
[1] [1]
3
74
M
PR
6
18
–
–
[1]
4
82
M
SD
2
8
–
Nephropathy
[2]
5
91
F
SD
2
11
–
Pancytopenia
[2]
6
82
F
PD
–
12
–
–
[2]
7
72
M
PR
4
7
–
–
[3]
8
54
M
PD
–
24?
–
–
[4]
9
64
M
SD
5
12
–
Abdominal pain
[5]
10
84
F
PR
10
20
–
–
[6]
11
64
M
SD
1.5
5
Radiation (before)
12
72
F
PR
5.3
51
–
13
82
M
PD
–
–
–
14
61
M
PR
14
16
Radiation
[7] G2 diarrhea, G3 leukopenia – G3 pancytopenia, G2 anorexia
[8] [9] [10]
15
78
F
PR
2
5
Radiation
–
[11]
16
70
F
SD
4
11
Radiation (before)
–
[12]
17
63
F
SD
4
12
–
G3 pancytopenia
[13]
18
67
M
PR
18
20
–
Mild phlebitis, mild nausea
[14]
19 20
72 64
M M
PR PR
6 13
10 13?
– –
– –
[15] [16]
21
73
M
PR
4
9
–
–
[17]
22
73
M
CR
24
40?
Radiation
–
[18]
CR complete response, PR partial response, SD stable disease, PD progressive disease
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Int J Clin Oncol
nausea), nephropathy (1), and phlebitis (1). Almost all toxicities were grade 1 or 2 except for 2 cases with grade 3 leukopenia or pancytopenia.
Although there are limitations to this review because cases without clinical effects are less likely to be reported, this regimen might be considered a relatively effective option for advanced EPD.
Discussion
Acknowledgments This study was supported in part by a National Cancer Center Research and Development Fund (23-A-22).
Extramammary Paget’s disease is a rare skin cancer generally affecting the genital region. Because the disorder is usually diagnosed as carcinoma in situ, the prognosis is generally favorable. However, the prognosis of patients with lymph node metastasis is extremely poor. Hatta et al. [19] reported that visceral metastasis occurred in 13 of 76 patients (17 %), and that 10 of these 13 patients (77 %) died of the disease. Despite the poor prognosis, the availability of systemic chemotherapy for advanced EPD has been limited. In 1990, Yokoyama et al. [20] reported a case of effective neoadjuvant chemotherapy consisting of mitomycin C, vincristine, and cisplatin. In 1992, Yamazaki et al. [21] reported combination chemotherapy consisting of 5-FU, epirubicin, carboplatin, vincristine, and mitomycin C, for which the clinical response was 3 PR and 5 SD (RR 37.5 %). Although the clinical effect of docetaxel has been reported, the number of examined cases is scant [22]. Two-thirds of the reported cases had shown some kind of clinical response. However this result could be higher than the actual value because cases without clinical effects are less likely to be reported. In the data from our hospital, 7 patients were treated and 3 PR (RR 43 %) were observed [2]. This review shows that there might be an association between clinical response and duration. The median duration of response with low-dose FP was 24 and 6 months in CR and PR patients, respectively, and longer than 3 months in SD patients. Furthermore, the median overall survival was 13 months in 13 patients showing CR or PR and longer than 11 months in SD patients. Because the toxicity of low-dose FP is relatively mild, this regimen hardly affected the quality of life even in older patients. Furthermore, palliative effects of low-dose FP have been reported. Otani et al. [8] reported that one patient showing PR had lived for over 4 years without hospitalization. Matsuura et al. [5] commented that lowdose FP could control pain and exudates from lesions. Ishizawa et al. [11] reported that this regimen was effective for carcinomatous lymphangiosis. Even in the cases showing SD, some authors stated that low-dose FP helped to maintain the patient’s quality of life and could contribute to the long-term survival with relief of symptoms. Because 2 of 3 patients showing PD had received other prior chemotherapy, low-dose FP may not work as second-line therapy [23].
Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Tokuda Y, Oguchi S, Yamazaki Y et al (1997) Low dose FP (5FU ? low-dose CDDP) therapy for advanced extramammary Paget’s disease. Jpn J Dermatol 107:21–27 (in Japanese) 2. Uhara H, Saida T (2003) Chemotherapy and immunotherapy for extramammary Paget’s disease and sweat gland carcinoma. Skin Cancer 18:92–98 (in Japanese) 3. Morita R, Kinbara T, Hatta N et al (1999) Low-dose FP therapy response in advanced extramammary Paget’s disease: a case report. Rinsyo Derma 41:1475–1477 (in Japanese) 4. Oguchi S, Kaneko M, Uhara H et al (2002) Docetaxel induced durable response in advanced extramammary Paget’s disease: a case report. J Dermatol 29:33–37 5. Mastuura A, Katakami C, Okuda F et al (2002) A case of extramammary Paget’s carcinoma with large tumor. Skin Cancer 17:189–192 (in Japanese) 6. Onishi I, Kamata T, Hayashi H et al (2002) A case of vulvar extramammary Paget’s disease associated with pancreatic cancer that was successfully treated with chemotherapy. Jpn Cancer Chemother 29:1973–1976 (in Japanese) 7. Uemura M, Mukai M, Fukuhara S et al (2002) A case of extramammary Paget’s disease with anuria. Acta Urol Jpn 48:311–314 (in Japanese) 8. Otani T, Endo S, Kato H et al (2003) A case of extramammary Paget’s carcinoma showing responsive to biochemical modulation chemotherapy. J Tokyo Women Med Univ 73:99–104 9. Inui S, Fukuhara S, Asada H et al (2000) Double involvement of extramammary Paget’s disease in genitalia and axilla. J Dermatol 27:409–412 10. Osawa R, Aoyagi S, Sawamura D et al (2005) A case of advanced extrramammary Paget’s carcinoma treated with low-dose FP (5FU ? CDDP) therapy and simultaneous radiotherapy. Skin Cancer 20:79–82 (in Japanese) 11. Ishizawa T, Konno T (2002) A case of extramammary Paget’s carcinoma whose chief complaint was reddening swelling on the left leg. Skin Cancer 17:234–237 (in Japanese) 12. Yokouchi M, Kobayashi M, Inazumi T (2007) A case of advanced axillary Paget’s disease. Rinsyo Hifuka 61:554–557 (in Japanese) 13. Kikuchi Y, Akita M, Kato S et al (2004) A case of advanced extramammary Paget’s disease treated with low-dose FP and internal PDT therapy. Jpn J Dermatol 114:1443 (in Japanese) 14. Kariya K, Tsuji T, Schwartz RA (2004) Trial of low-dose 5-fluorouracil/cisplatin therapy for advanced extramammary Paget’s disease. Dermatol Surg 30:341–344 15. Harasima T, Sinokawa Y, Himi Y (2007) The experience of treatment of recurrence extramammary Paget’s disease by lowdose FP therapy. J Jpn P R S 27:535 (in Japanese) 16. Shibuya Y, Arakawa C, Suzuki S et al (2008) Low-dose FP: an effective treatment of advanced extramammary Paget’s disease. Skin Cancer 23:375–378 (in Japanese)
123
Int J Clin Oncol 17. Yamamoto A, Yoneyama K, Ono S et al (2010) A case of secondary extramammary Paget’s disease. Tokyo J Obstet Gynecol 59:78–82 (in Japanese) 18. Yamada N, Kusakabe S, Tukamoto K et al (2010) Three cases of advanced extramammary Paget’s disease treated by chemo–radio therapy. Jpn J Dermatol 120:728 (in Japanese) 19. Hatta N, Yamada T, Hirono T et al (2008) Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol 158:313–318 20. Yokoyama Y, Mabuchi M, Kawabata I et al (1990) Metastatic vulvar Paget’s disease responding to combination chemotherapy. Jpn J Clin Oncol 20:426–430
123
21. Yamazaki N, Yamamoto A, Wada T et al (1999) A case of metastatic extramammary Paget’s disease that responded to combination chemotherapy. J Dermatol 26:311–316 22. Kurooka S, Namikawa K, Tsutsumida A et al (2012) A statistical study of 101 patients with extramammary Paget’s disease. Jpn J Dermatol 122:2891–2897 (in Japanese) 23. Mkoshiba Y, Uhara H, Kubo H et al (2013) S-1 induced a durable response in metastatic extramammary Paget’s disease. J Dermatol 40:664–665
