Annual Report 2020

Department of Dermatologic Oncology

Naoya Yamazaki, Akira Takahashi, Kenjiro Namikawa, Dai Ogata, Shunichi Jinnai

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. Over 4,000 cases of malignant melanoma have been accumulated thus far; this is an impressive number for a hospital or research institution in Japan. Today, patients are referred from all over Japan. Most of these patients are examined and treated for skin cancer, including malignant melanoma. Surgery is the main treatment modality for skin cancer, and multi-disciplinary treatments, consisting of immunotherapy, targeted therapy, chemotherapy, and radiotherapy, are also routinely performed. However, the importance of immunotherapy is currently increasing. Melanoma is at the center of immune therapy development. This department plays an active role in multicenter trials for new skin cancer agents throughout Japan.

The Team and What We Do

 The department has four dermatologic oncologists, one chief resident and five residents. We are also engaged in routine outpatient activities on Wednesdays and Thursdays in the National Cancer Center Hospital 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 resulted from the creation of a national network to develop treatment for malignant skin tumors. In addition, 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.

Table 1. Number of New Patients 

 At any one time, about 14 patients are hospitalized to undergo surgery, chemotherapy, or radiation therapy. In 2019, 241 operations were performed including 137 operations under general anesthesia.

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

 The 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 the BRAF-mutation status.

 For almost all patients with BRAF-mutated metastatic disease, the BRAF-targeted therapy first-line options include BRAF/MEK inhibitor combination therapy with dabrafenib/trametinib or encorafenib/binimetinib.

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

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

 This year, our hospital and patient numbers were impacted by COVID-19. Nevertheless, the number of patients with angiosarcoma and extramammary Paget’s disease is increasing each year in the dermatology oncology department.

Research activities

 Malignant skin tumors are primarily treated with surgery (Appended Table 2). However, in recent years, several new drugs for the treatment of malignant melanoma have been rapidly developed overseas. Our department is conducting many clinical studies and trials; the major ones are described as follows:

• A study of the prognosis of malignant melanoma and the relevant gene expressions in the tumor.
• 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.
• Confirmatory trial of narrower side margins for basal cell carcinoma in the Japanese population. (JCOG2005)
• A multinational Phase III clinical trial of nivolumab in combination with anti-LAG-3 antibody for advanced malignant melanoma.
• Prognosis of melanoma patients with a complete response to anti-PD-1 therapy.

Table 2. Operative Procedures (total number) in 2020/4 – 2021/3

Table 3. New Agent Studies in 2020

Clinical trials

 Table 3 presents the summary of our clinical trials.

Education

 Currently, training in routine clinical practice under skilled guidance is ongoing for one chief resident and five resident physicians. In addition, conferences with the departments of oncology, radiotherapy and pathology are held on a regular basis. They made a total of 13 presentations in domestic academic conferences, and published seven papers, twelve 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, the Department of Radiation Oncology is developing a linear accelerator for hospital-based boron neutron capture therapy (BNCT) as a new radiotherapy. We are participating in this trial for angiosarcoma and melanoma.

 Meanwhile, we are developing treatments for advanced squamous cell carcinoma and angiosarcoma with immune checkpoint inhibitors.

List of papers published in 2020

Journal

1. Nishino K, Fujiwara Y, Ohe Y, Saito R, Miyauchi E, Kobayashi T, Nakai Y, Takahashi T, Shibata T, Hamaguchi T, Kikuchi K, Yamazaki N, Fukuda H, Nozawa K, Kiyohara Y. Results of the non-small cell lung cancer part of a phase III, open-label, randomized trial evaluating topical corticosteroid therapy for facial acneiform dermatitis induced by EGFR inhibitors: stepwise rank down from potent corticosteroid (FAEISS study, NCCH-1512). Support Care Cancer, 29:2327-2334, 2021

2. Tsutsui K, Namikawa K, Mori T, Kato K, Jinnai S, Nakama K, Ogata D, Takahashi A, Yamazaki N. Case of acquired reactive perforating collagenosis induced by panitumumab for colon cancer. J Dermatol, 48:e114-e115, 2021

3. Mizuta H, Namikawa K, Takahashi A, Ogata D, Muto Y, Jinnai S, Nakama K, Tsutsui K, Yamazaki N. The first case of a collision tumor of melanotrichoblastoma and seborrheic keratosis. Int J Dermatol, 60:e54-e56, 2021

4. Mizuta H, Namikawa K, Nakama K, Yamazaki N. Intramedullary spinal cord metastasis of malignant melanoma:Two cases with rim signs in contrast-enhanced magnetic resonance imaging: A case report. Mol Clin Oncol, 14:47, 2021

5. Ogata D, Haydu LE, Glitza IC, Patel SP, Tawbi HA, McQuade JL, Diab A, Ekmekcioglu S, Wong MK, Davies MA, Amaria RN. The efficacy of anti-programmed cell death protein 1 therapy among patients with metastatic acral and metastatic mucosal melanoma. Cancer Med, 10:2293-2299, 2021

6. Ding Z, Ogata D, Roszik J, Qin Y, Kim SH, Tetzlaff MT, Lazar AJ, Davies MA, Ekmekcioglu S, Grimm EA. iNOS Associates With Poor Survival in Melanoma: A Role for Nitric Oxide in the PI3K-AKT Pathway Stimulation and PTEN S-Nitrosylation. Front Oncol, 11:631766, 2021

7. Ogata D, Namikawa K, Takahashi A, Yamazaki N. A review of the AJCC melanoma staging system in the TNM classification (eighth edition). Jpn J Clin Oncol, 51:671-674, 2021

8. Tsutsui K, Kikuchi K, Nozawa K, Takashima A, Tsuchiyama K, Namikawa K, Aiba S, Yamazaki N. Efficacy and safety of topical benzoyl peroxide for prolonged acneiform eruptions induced by cetuximab and panitumumab: A multicenter, phase II trial. J Dermatol, 2021

9. Uhara H, Kiyohara Y, Uehara J, Fujisawa Y, Takenouchi T, Otsuka M, Uchi H, Fukushima S, Minami H, Hatsumichi M, Yamazaki N. Five-year survival with nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma. J Dermatol, 48:592-599, 2021

10. Nakama K, Ogata D, Nakano E, Tsutsui K, Jinnai S, Namikawa K, Takahashi A, Yamazaki N. Clinical response to a MEK inhibitor in a patient with metastatic melanoma harboring an RAF1 gene rearrangement detected by cancer gene panel testing. J Dermatol, 48:e256-e257, 2021

11. Muto Y, Ryo E, Namikawa K, Takahashi A, Ogata D, Fujimura T, Yatabe Y, Aiba S, Yamazaki N, Mori T. RB1 gene mutations are a distinct predictive factor in Merkel cell carcinoma. Pathol Int, 71:337-347, 2021

12. Jinnai S, Yamazaki N, Hirano Y, Sugawara Y, Ohe Y, Hamamoto R. The Development of a Skin Cancer Classification System for Pigmented Skin Lesions Using Deep Learning. Biomolecules, 10:2020

13. Hashimoto H, Iwasa S, Yanai-Takahashi T, Honma Y, Kato K, Hamaguchi T, Yamada Y, Shimada Y, Yamazaki N, Kato Y. Randomized, Double-Blind, Placebo-Controlled Phase II Study on the Efficacy and Safety of Vitamin K1 Ointment for Cetuximab or Panitumumab-Induced Acneiform Eruptions-VIKTORIA Study. Gan To Kagaku Ryoho, 47:933-939, 2020

14. Zenda S, Ryu A, Takashima A, Arai M, Takagi Y, Miyaji T, Mashiko T, Shimizu Y, Yamazaki N, Morizane C, Yamaguchi T, Kawaguchi T, Hanai A, Uchitomi Y, Oshiba F. Hydrocolloid dressing as a prophylactic use for hand-foot skin reaction induced by multitargeted kinase inhibitors: protocol of a phase 3 randomised self-controlled study. BMJ Open, 10:e038276, 2020

15. Nakano E, Takahashi A, Namikawa K, Muto Y, Jinnai S, Kage Y, Mizuta H, Tsutsumida A, Yamazaki N. Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab: A single institutional retrospective study. J Dermatol, 47:622-628, 2020

16. 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

17. 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

18. Hirano G, Nemoto M, Kimura Y, Kiyohara Y, Koga H, Yamazaki N, Christensen G, Ingvar C, Nielsen K, Nakamura A, Sota T, Nagaoka T. Automatic diagnosis of melanoma using hyperspectral data and GoogLeNet. Skin Res Technol, 26:891-897, 2020

19. Tsutsui K, Takahashi A, Muto Y, Mizuta H, Jinnai S, Nakama K, Ogata D, Namikawa K, Yamazaki N. Outcomes of lymph node dissection in the treatment of extramammary Paget's disease: A single-institution study. J Dermatol, 47:512-517, 2020

20. Oashi K, Shibata T, Namikawa K, Takahashi A, Yokota K, Nakano E, Teramoto Y, Tsutsumida A, Maeda T, Yamazaki N. A single-arm confirmatory trial of pazopanib in patients with paclitaxel-pretreated primary cutaneous angiosarcoma: Japan Clinical Oncology Group study (JCOG1605, JCOG-PCAS protocol). BMC Cancer, 20:652, 2020

21. Mizuta H, Takahashi A, Namikawa K, Ogata D, Yamazaki N. Association between prognosis and complete resection in primary cutaneous myoepithelial carcinoma: two case presentations and literature review. Dermatol Ther, 33:e13485, 2020

22. Takahashi A, Namikawa K, Ogata D, Nakano E, Jinnai S, Nakama K, Tsutsui K, Muto Y, Mizuta H, Yamazaki N. Real-world efficacy and safety data of nivolumab and ipilimumab combination therapy in Japanese patients with advanced melanoma. J Dermatol, 47:1267-1275, 2020

23. Watanabe R, Okano S, Yamazaki N. Fixed drug eruption dramatically exacerbated during treatment with programmed death 1 inhibitor. J Dermatol, 47:e425-e426, 2020

24. Namikawa K, Kiyohara Y, Takenouchi T, Uhara H, Uchi H, Yoshikawa S, Takatsuka S, Koga H, Wada N, Minami H, Hatsumichi M, Namba Y, Yamazaki N. Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma. J Dermatol, 47:1257-1266, 2020

25. Tsutsui K, Namikawa K, Mori T, Jinnai S, Nakama K, Ogata D, Takahashi A, Yamazaki N. Case of multiple ectopic extramammary Paget's disease of the trunk. J Dermatol, 47:e329-e331, 2020

26. Kumagai S, Togashi Y, Kamada T, Sugiyama E, Nishinakamura H, Takeuchi Y, Vitaly K, Itahashi K, Maeda Y, Matsui S, Shibahara T, Yamashita Y, Irie T, Tsuge A, Fukuoka S, Kawazoe A, Udagawa H, Kirita K, Aokage K, Ishii G, Kuwata T, Nakama K, Kawazu M, Ueno T, Yamazaki N, Goto K, Tsuboi M, Mano H, Doi T, Shitara K, Nishikawa H. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol, 21:1346-1358, 2020

27. Yamazaki N, Kiyohara Y, Uhara H, Tsuchida T, Maruyama K, Shakunaga N, Itakura E, Komoto A. Real-world safety and efficacy data of ipilimumab in Japanese radically unresectable malignant melanoma patients: A postmarketing surveillance. J Dermatol, 47:834-848, 2020

28. Dummer R, Lebb? C, Atkinson V, Mandal? M, Nathan PD, Arance A, Richtig E, Yamazaki N, Robert C, Schadendorf D, Tawbi HA, Ascierto PA, Ribas A, Flaherty KT, Pakhle N, Campbell CD, Gusenleitner D, Masood A, Brase JC, Gasal E, Long GV. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat Med, 26:1557-1563, 2020

29. Ishii M, Hirai I, Tanese K, Fusumae T, Nakamura Y, Fukuda K, Uchi H, Kabashima K, Otsuka A, Yokota K, Yamazaki N, Namikawa K, Fujimura T, Takenouchi T, Yamamoto Y, Nishiguchi M, Sato Y, Amagai M, Funakoshi T. Anti-PD-1 antibody therapy for epithelial skin malignancies: An investigator-initiated, open-label, single-arm, multicenter, phase II clinical trial (NMSC-PD1 Study). Medicine (Baltimore), 99:e22913, 2020

30. Kasuga K, Sakamoto T, Takamaru H, Sekiguchi M, Yamada M, Yamazaki N, Hashimoto T, Uraoka T, Saito Y. Endoscopic reduction of colocolonic intussusception due to metastatic malignant melanoma: A case report. World J Clin Cases, 8:5816-5820, 2020

31. Kawada M, Nobeyama Y, Goto Y, Nakama K, Yamazaki N, Asahina A. Absence of toxic epidermal necrolysis recurrence with pembrolizumab re-challenge in a patient with a positive lymphocyte transformation test. J Dermatol, 47:e424-e425, 2020