Annual Report 2019

Department of Dermatologic Oncology

Naoya Yamazaki, Akira Takahashi, Kenjiro Namikawa, Eiji Nakano, Dai Ogata, Haruki Mizuta

Introduction

 The Department of Dermatologic Oncology has consistently served as the core hospital for the establishment of treatment strategies for malignant skin tumors since the National Cancer Center opened in 1962, and over 4,000 cases of malignant melanoma have been accumulated thus far, an impressive number for a hospital or research institution in Japan. Today, patients are referred from throughout Japan. Of particular note, the number of patients with malignant melanoma was 200, which was approximately twice the number 10 years ago (Table 1). Most of the patients are examined and treated for skin cancer including malignant melanoma. Surgery is the main treatment modality for skin cancer, and multidisciplinary treatments, consisting of immunotherapy, targeted therapy, chemotherapy, and radiotherapy, are also routinely carried out. But these days, especially, the importance of immunotherapy is increasing. Melanoma is at the center of development of immune therapy. This department plays an active role in multicenter trials for new agents for skin cancer all over Japan.

The Team and What We Do

 The Department has four staff dermatologic oncologists and five residents. We are also engaged in routine outpatient activities on Wednesdays and Thursdays in the National Cancer Center East.

 Our department is a high-volume center, where we have seen an average of 180 patients with malignant melanoma annually in the last 5 years. This is the result of the creation of a national network to develop treatment for malignant skin tumors, and nivolumab, an anti- PD-1 antibody, was approved as a therapeutic agent for malignant melanoma in Japan for the first time in the world as a result of vigorous development of new drugs.

 At all times, about 20 patients are hospitalized to undergo surgery, chemotherapy, or radiation therapy. In 2019, 268 operations were performed including 126 operations under general anesthesia.

 For first-line systemic therapy of unresectable or metastatic melanoma, recommended treatment options include checkpoint immunotherapy, BRAF-targeted therapy for patients with BRAF-mutated disease, or clinical trials.

 Checkpoint immunotherapy options in this setting include anti-PD-1 monotherapy or a combination of ipilimumab and nivolumab.

 Checkpoint inhibitors have been shown to be effective regardless of BRAF-mutation status.

 For almost all patients with BRAF-mutant metastatic disease, BRAF-targeted therapy first-line options include BRAF/MEK inhibitor combination therapy with dabrafenib/trametinib.

 Rounds are made and case presentations are held every morning. A weekly division conference is held every Monday to discuss the therapeutic principles for outpatients and inpatients. A clinicopathological conference that focuses on surgically removed skin specimens is held with pathologists once a month.

 In addition, we have treated advanced cases of mucosal melanoma patients in the nasal cavity, genital lesions, perianal lesions, and uveal melanoma even though our origins are “dermatologic”.

Table 1. Number of New Patients

Research activities

 Malignant skin tumors are mainly treated by surgery (appended Table 2). However, in recent years, several new drugs have been developed rapidly overseas for the treatment of malignant melanoma, and our department is conducting many clinical studies and trials; the major ones are described below.

• A study of the prognosis of malignant melanoma and the relevant gene expressions in the tumor
• A confirmatory trial of non-amputative digit preservation surgery for subungual melanoma (JCOG1602; J-NAIL study)
• A single-arm confirmatory trial of pazopanib in patients with paclitaxel-pretreated primary cutaneous angiosarcoma (JCOG1605)
• Real-world efficacy of anti-PD-1 antibodies in advanced acral melanoma patients: a retrospective, multicenter study (JAMP study)
• A phase I clinical trial of intratumoral administration of GEN0101 in patients with advanced malignant melanoma
• A clinical trial of oncolytic virus treatment in patients with advanced cutaneous melanoma
• A multinational phase III clinical trial of nivolumab in combination with anti-LAG-3 antibody for advanced malignant melanoma

Table 2. Operative Procedures (total number) in 2019/4 - 2020/3

Clinical trials

 Table3 shows our clinical trials.

Table 3. New Agent Studies in 2019

Education

 Currently, training in routine clinical practice under skilled guidance is ongoing for five resident physicians. In addition, conferences with the departments of oncology, radiotherapy and pathology are held on a regular basis. The resident physicians and the oncology trainee made a total of 14 presentations in domestic academic conferences and one presentation in international academic conferences and also published seven papers, five of which were international academic papers in English.

Future prospects

 With the continuing rapid progress in drug therapy for advanced cutaneous malignant melanoma, we are now facing an era where the indications of drug therapy for malignant melanoma are being expanded to include combination therapies and adjuvant therapies.

 In addition to these, the Department of Radiation Oncology is developing a linear accelerator for the hospital-based boron neutron capture therapy (BNCT) as a new radiotherapy. We are planning to participate in this trail.

 On the other hand, information and treatment options are limited for squamous cell carcinoma even though it is one of the typical skin cancers. Therefore, we are scheduled to participate in an international joint clinical trial of the anti-PD-1 antibody cemiplimab.

List of papers published in 2019

Journal

1. Tsutsui K, Namikawa K, Takahashi A, Yamazaki N. Reconstruction with scrotal flap for extramammary Paget's disease of the groin, penis, and scrotum: a single-institution case series. Int J Dermatol, 59:e62-e64, 2020

2. Tsutsui K, Takahashi A, Namikawa K, Yamazaki N. Advanced extramammary Paget disease treated with neoadjuvant chemotherapy: A report of two cases. Australas J Dermatol, 61:e105-e107, 2020

3. Namikawa K, Takahashi A, Mori T, Tsutsumida A, Suzuki S, Motoi N, Jinnai S, Kage Y, Mizuta H, Muto Y, Nakano E, Yamazaki N. Nivolumab for patients with metastatic uveal melanoma previously untreated with ipilimumab: a single-institution retrospective study. Melanoma Res, 30:76-84, 2020

4. Kato K, Nemoto M, Kimura Y, Kiyohara Y, Koga H, Yamazaki N, Christensen G, Ingvar C, Nielsen K, Nakamura A, Sota T, Nagaoka T. Performance improvement of automated melanoma diagnosis system by data augmentation. Advanced Biomedical Engineering, 2020

5. Mizuta H, Nakano E, Takahashi A, Koyama T, Namikawa K, Yamazaki N. Hemophagocytic lymphohistiocytosis with advanced malignant melanoma accompanied by ipilimumab and nivolumab: A case report and literature review. Dermatol Ther, 33:e13321, 2020

6. Namikawa K, Takahashi A, Mori T, Tsutsumida A, Suzuki S, Motoi N, Jinnai S, Kage Y, Mizuta H, Muto Y, Nakano E, Yamazaki N. Nivolumab for patients with metastatic uveal melanoma previously untreated with ipilimumab: a single-institution retrospective study. Melanoma Res, 30:76-84, 2020

7. Muto Y, Namikawa K, Fujiwara Y, Mori T, Nakano E, Takahashi A, Yamazaki N. Bullous pemphigoid induced by pembrolizumab in a patient with non-small-cell lung cancer who achieved durable complete response despite treatment cessation and long-term corticosteroid administration: A case report. J Dermatol, 47:e9-e11, 2020

8. Tsutsui K, Takahashi A, Namikawa K, Yamazaki N. Advanced extramammary Paget disease treated with neoadjuvant chemotherapy: A report of two cases. Australas J Dermatol, 61:e105-e107, 2020

9. Mizuta H, Takahashi A, Mori T, Namikawa K, Nakano E, Muto Y, Jinnai S, Nakama K, Tsutsui K, Yamazaki N. Efficacy of oral retinoids for keratoacanthoma centrifugum marginatum. Dermatol Ther, 33:e13291, 2020

10. Ogata D, Namikawa K, Otsuka M, Asai J, Kato H, Yasuda M, Maekawa T, Fujimura T, Kato J, Takenouchi T, Nagase K, Kawaguchi M, Kaji T, Kuwatsuka Y, Shibayama Y, Takai T, Okumura M, Kambayashi Y, Yoshikawa S, Yamazaki N, Tsuchida T. Systemic treatment of patients with advanced cutaneous squamous cell carcinoma: response rates and outcomes of the regimes used. Eur J Cancer, 127:108-117, 2020

11. Tsutsui K, Namikawa K, Takahashi A, Yamazaki N. Reconstruction with scrotal flap for extramammary Paget's disease of the groin, penis, and scrotum: a single-institution case series. Int J Dermatol, 59:e62-e64, 2020

12. Tsutsui K, Takahashi A, Mori T, Namikawa K, Yamazaki N. Secretory carcinoma of the skin arising on the eyelid, distinguished by immunohistochemical markers and fluorescence in situ hybridization. J Dermatol, 47:e99-e100, 2020

13. Takahashi A, Namikawa K, Nakano E, Yamazaki N. Real-world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced melanoma. J Dermatol, 47:257-264, 2020

14. Sekine S, Kiyono T, Ryo E, Ogawa R, Wakai S, Ichikawa H, Suzuki K, Arai S, Tsuta K, Ishida M, Sasajima Y, Goshima N, Yamazaki N, Mori T. Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma. J Clin Invest, 130:3827-3832, 2019

15. Watanabe R, Nakano E, Kawazoe A, Kuboki Y, Bando H, Shitara K, Takahashi A, Tsutsumida A, Nishizawa A, Yamazaki N. Four cases of paradoxical cephalocervical pyogenic granuloma during treatment with paclitaxel and ramucirumab. J Dermatol, 46:e178-e180, 2019

16. Yamazaki N, Kiyohara Y, Uhara H, Uehara J, Fujisawa Y, Takenouchi T, Otsuka M, Uchi H, Ihn H, Hatsumichi M, Minami H. Long-term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma. Cancer Sci, 110:1995-2003, 2019

17. Muto Y, Kitano S, Tsutsumida A, Namikawa K, Takahashi A, Nakamura Y, Yamanaka T, Yamamoto N, Yamazaki N. Investigation of clinical factors associated with longer overall survival in advanced melanoma patients treated with sequential ipilimumab. J Dermatol, 46:498-506, 2019

18. Baba T, Sakai F, Kato T, Kusumoto M, Kenmotsu H, Sugiura H, Tominaga J, Oikado K, Sata M, Endo M, Yanagawa N, Sasaki S, Iwasawa T, Saito Y, Fujiwara Y, Ohe Y, Yamazaki N, Sakamoto T, Koshiba T, Kuwano K. Radiologic features of pneumonitis associated with nivolumab in non-small-cell lung cancer and malignant melanoma. Future Oncol, 15:1911-1920, 2019

19. Ishida H, Shimizu Y, Sakaguchi H, Nitanda H, Kaneko K, Yamazaki N, Yanagihara A, Taguchi R, Sakai F, Yasuda M, Kobayashi K. Distinctive clinicopathological features of adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung: A retrospective study. Lung Cancer, 129:16-21, 2019

20. Yamaguchi K, Komatsu Y, Satoh T, Uetake H, Yoshino T, Nishida T, Yamazaki N, Takikawa H, Morimoto T, Chosa M, Sunaya T, Hamada Y, Muro K, Sugihara K. Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting. Oncologist, 24:e450-e457, 2019

21. Kinoshita T, Nakayama T, Fukuma E, Inokuchi M, Ishiguro H, Ogo E, Kikuchi M, Jinno H, Yamazaki N, Toi M. Efficacy of Scalp Cooling in Preventing and Recovering From Chemotherapy-Induced Alopecia in Breast Cancer Patients: The HOPE Study. Front Oncol, 9:733, 2019

22. Gogas HJ, Flaherty KT, Dummer R, Ascierto PA, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Sileni VC, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Gollerkeri A, Pickard MD, Robert C. Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management. Eur J Cancer, 119:97-106, 2019

23. Tanaka K, Nakamura Y, Mizutani T, Shibata T, Tsutsumida A, Fukuda H, Matsushita S, Aoki M, Namikawa K, Ohe S, Fukushima S, Yamazaki N. Confirmatory trial of non-amputative digit preservation surgery for subungual melanoma: Japan Clinical Oncology Group study (JCOG1602, J-NAIL study protocol). BMC Cancer, 19:1002, 2019

24. Tsutsumida A, Fukushima S, Yokota K, Yoshikawa S, Yamasaki O, Tanemura A, Okuyama R, Uhara H, Muto Y, Miyashita A, Akiyama M, Kaji T, Koga H, Kato J, Katayama T, Itakura E, Yamazaki N, Kiyohara Y. Japanese real-world study of sequential nivolumab and ipilimumab treament in melanoma. J Dermatol, 46:947-955, 2019

25. Yokota K, Uchi H, Uhara H, Yoshikawa S, Takenouchi T, Inozume T, Ozawa K, Ihn H, Fujisawa Y, Qureshi A, de Pril V, Otsuka Y, Weber J, Yamazaki N. Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: Japanese subgroup analysis from the phase 3 CheckMate 238 study. J Dermatol, 46:1197-1201, 2019

26. Sekimizu M, Yoshida A, Mitani S, Asano N, Hirata M, Kubo T, Yamazaki F, Sakamoto H, Kato M, Makise N, Mori T, Yamazaki N, Sekine S, Oda I, Watanabe SI, Hiraga H, Yonemoto T, Kawamoto T, Naka N, Funauchi Y, Nishida Y, Honoki K, Kawano H, Tsuchiya H, Kunisada T, Matsuda K, Inagaki K, Kawai A, Ichikawa H. Frequent mutations of genes encoding vacuolar H+ -ATPase components in granular cell tumors. Genes Chromosomes Cancer, 58:373-380, 2019

27. Muto Y, Kitano S, Tsutsumida A, Namikawa K, Takahashi A, Nakamura Y, Yamanaka T, Yamamoto N, Yamazaki N. Investigation of clinical factors associated with longer overall survival in advanced melanoma patients treated with sequential ipilimumab. J Dermatol, 46:498-506, 2019

28. Baba T, Sakai F, Kato T, Kusumoto M, Kenmotsu H, Sugiura H, Tominaga J, Oikado K, Sata M, Endo M, Yanagawa N, Sasaki S, Iwasawa T, Saito Y, Fujiwara Y, Ohe Y, Yamazaki N, Sakamoto T, Koshiba T, Kuwano K. Radiologic features of pneumonitis associated with nivolumab in non-small-cell lung cancer and malignant melanoma. Future Oncol, 15:1911-1920, 2019

29. Kinoshita T, Nakayama T, Fukuma E, Inokuchi M, Ishiguro H, Ogo E, Kikuchi M, Jinno H, Yamazaki N, Toi M. Efficacy of Scalp Cooling in Preventing and Recovering From Chemotherapy-Induced Alopecia in Breast Cancer Patients: The HOPE Study. Front Oncol, 9:733, 2019

30. Watanabe R, Nakano E, Kawazoe A, Kuboki Y, Bando H, Shitara K, Takahashi A, Tsutsumida A, Nishizawa A, Yamazaki N. Four cases of paradoxical cephalocervical pyogenic granuloma during treatment with paclitaxel and ramucirumab. J Dermatol, 46:e178-e180, 2019

31. Yamazaki N, Kiyohara Y, Uhara H, Uehara J, Fujisawa Y, Takenouchi T, Otsuka M, Uchi H, Ihn H, Hatsumichi M, Minami H. Long-term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma. Cancer Sci, 110:1995-2003, 2019

32. Sekine S, Kiyono T, Ryo E, Ogawa R, Wakai S, Ichikawa H, Suzuki K, Arai S, Tsuta K, Ishida M, Sasajima Y, Goshima N, Yamazaki N, Mori T. Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma. J Clin Invest, 129:3827-3832, 2019

33. Yamaguchi K, Komatsu Y, Satoh T, Uetake H, Yoshino T, Nishida T, Yamazaki N, Takikawa H, Morimoto T, Chosa M, Sunaya T, Hamada Y, Muro K, Sugihara K. Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting. Oncologist, 24:e450-e457, 2019

34. Gogas HJ, Flaherty KT, Dummer R, Ascierto PA, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Sileni VC, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Gollerkeri A, Pickard MD, Robert C. Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management. Eur J Cancer, 119:97-106, 2019

35. Tanaka K, Nakamura Y, Mizutani T, Shibata T, Tsutsumida A, Fukuda H, Matsushita S, Aoki M, Namikawa K, Ohe S, Fukushima S, Yamazaki N. Confirmatory trial of non-amputative digit preservation surgery for subungual melanoma: Japan Clinical Oncology Group study (JCOG1602, J-NAIL study protocol). BMC Cancer, 19:1002, 2019

36. Tsutsumida A, Fukushima S, Yokota K, Yoshikawa S, Yamasaki O, Tanemura A, Okuyama R, Uhara H, Muto Y, Miyashita A, Akiyama M, Kaji T, Koga H, Kato J, Katayama T, Itakura E, Yamazaki N, Kiyohara Y. Japanese real-world study of sequential nivolumab and ipilimumab treament in melanoma. J Dermatol, 46:947-955, 2019

37. Yokota K, Uchi H, Uhara H, Yoshikawa S, Takenouchi T, Inozume T, Ozawa K, Ihn H, Fujisawa Y, Qureshi A, de Pril V, Otsuka Y, Weber J, Yamazaki N. Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: Japanese subgroup analysis from the phase 3 CheckMate 238 study. J Dermatol, 46:1197-1201, 2019

38. Fujisawa Y, Yoshikawa S, Minagawa A, Takenouchi T, Yokota K, Uchi H, Noma N, Nakamura Y, Asai J, Kato J, Fujiwara S, Fukushima S, Uehara J, Hoashi T, Kaji T, Fujimura T, Namikawa K, Yoshioka M, Murao N, Ogata D, Matsuyama K, Hatta N, Shibayama Y, Fujiyama T, Ishikawa M, Yamada D, Kishi A, Nakamura Y, Shimiauchi T, Fujii K, Fujimoto M, Ihn H, Katoh N. Clinical and histopathological characteristics and survival analysis of 4594 Japanese patients with melanoma. Cancer Med, 8:2146-2156, 2019

39. Namikawa K, Aung PP, Milton DR, Tetzlaff MT, Torres-Cabala CA, Curry JL, Nagarajan P, Ivan D, Ross M, Gershenwald JE, Prieto VG. Correlation of Tumor Burden in Sentinel Lymph Nodes with Tumor Burden in Nonsentinel Lymph Nodes and Survival in Cutaneous Melanoma. Clin Cancer Res, 25:7585-7593, 2019

40. Fujisawa Y, Yoshikawa S, Minagawa A, Takenouchi T, Yokota K, Uchi H, Noma N, Nakamura Y, Asai J, Kato J, Fujiwara S, Fukushima S, Uehara J, Hoashi T, Kaji T, Fujimura T, Namikawa K, Yoshioka M, Murata N, Ogata D, Matsuyama K, Hatta N, Shibayama Y, Fujiyama T, Ishikawa M, Yamada D, Kishi A, Nakamura Y, Shimiauchi T, Fujii K, Fujimoto M, Ihn H, Katoh N. Classification of 3097 patients from the Japanese melanoma study database using the American joint committee on cancer eighth edition cancer staging system. J Dermatol Sci, 94:284-289, 2019