Annual Report 2021

Department of Head and Neck, Esophageal Medical Oncology

Ken Kato, Yoshitaka Honma, Shun Yamamoto, Kazuki Yokoyama

Introduction

 The Department of Head and Neck, Esophageal Medical Oncology focuses on the development of new drugs and establishment of standard chemotherapy regimens, including multimodality treatment with surgery and/or radiotherapy for advanced head and neck cancers (HNCs), consisting of malignancies arising from the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, nasal/paranasal cavity, salivary gland, ear canal, thyroid and so on. We also focus on the multimodality treatment of esophageal cancer (EC), mainly chemotherapy and chemoradiotherapy. The main histology of HNC and EC is squamous cell carcinoma. However, there is still a wide variety of histological types, especially in the nasal/paranasal cavity, salivary glands, and gastroesophageal-junctional cancer. Therefore, pathological diagnosis is essential, making a treatment strategy based on pathological findings significant in advanced HNCs and ECs.

The Team and What We Do

 The staff of the Department of Head and Neck, Esophageal Medical Oncology consists of 4 medical oncologists. We hold a daily case conference together at 6 pm after finishing routine clinical work and also hold a monthly research conference and discuss the progress of clinical trials or in-house research. Intergroup meetings with the Departments of Head and Neck Surgery, Esophageal Surgery, Endoscopy, Radiation Oncology, Diagnostic Radiology, and Diagnostic Pathology are held weekly to decide optimal treatment strategies for each individual case and to discuss treatment consensus for the disease. In 2021, we treated 505 hospitalized patients (206 of whom were newly diagnosed), including 292 with esophageal/esophagogastric junction cancer, 58 with hypopharyngeal cancer, 15 with oropharyngeal cancer, 10 with nasopharyngeal cancer, and 29 with tongue cancer. Rare cancers of the head and neck region, such as undifferentiated thyroid cancer and salivary gland cancer, have also been treated through referrals from other hospitals. Of these patients, 65 were entered into clinical trials.

Research activities

 A trans-oral/percutaneous biopsy and blood sampling before and after cetuximab and nivolumab provide an excellent opportunity to study biomarkers. We are collecting these fresh samples from patients with HNSCC to evaluate the correlations between gene expression or immunogenic profiles and patients’ outcomes by using genome sequencing, immune-panel, microarray, or real-time PCR techniques.

 We have also been measuring the gene expressions of possible predictive biomarkers by using FFPE samples obtained from surgical resection or trans-oral/percutaneous biopsy. These studies are being performed in collaboration with the Center for Medical Genomics, National Cancer Center Research Institute (NCCRI), or other institutions.

 We have performed an investigator-initiated trial (FRONTiER study) regarding patients with locally resectable esophageal squamous cell carcinoma, to evaluate the safety and efficacy of neoadjuvant chemotherapy with nivolumab. Along with this multicenter trial, biomarker analysis of immunotherapy using biopsy samples, fecal samples and other methods has been conducted with collaborators at NCCRI or other institutions. The results were presented in the ASCO-GI meeting. In addition, the results of a comparative study of preoperative treatment for resectable esophageal cancer (JCOG1109) conducted by Kato at JCOG were presented at the Oral Session at ASCO-GI 2022.

 The results of the global CheckMate-648 study (a study demonstrating the add-on effect of nivolumab and the superiority of nivolumab + ipilimumab combination therapy in first-line chemotherapy patients for esophageal cancer) were published in the New England Journal of Medicine. Kato participated as a corresponding author.

Table 1. Clinical trials and the number of registered patients.

Clinical trials

 We carried out clinical trials in collaboration with the Departments of Head and Neck Surgery, Esophageal Surgery, Gastrointestinal Endoscopy, Radiation Oncology, Diagnostic Radiology, and Diagnostic Pathology in our hospital. Details of clinical trials are summarized in the Table, including JCOG (Japan Clinical Oncology Group) trials, company-initiated trials, and other collaborative investigator-initiated trials. The list of trials conducted in our department and the number of registrations are shown (Table 1).

Education

 Residents and staff make rounds every day and provide on-the-job education. Each staff member conducts lectures for residents every three months, and also distributes them as ZOOM and video archives to facilities with former residents and related facilities. Residents made 7 presentations in Japan and 4 overseas, and published 4 papers in English.

Future Prospects

 We are conducting investigator-initiated clinical trials to examine the usefulness of nivolumab in preoperative treatment for esophageal cancer, and we have also enrolled a large number of patients in investigator-initiated clinical trials for salivary gland cancer in the field of head and neck cancer. In addition, we are currently discussing with a company about conducting a doctor-initiated clinical trial of a combination therapy of photoimmunotherapy and an immune checkpoint inhibitor. We are also conducting joint research with China on investigator-initiated clinical trials of CDK4/6 inhibitors for esophageal cancer. In addition, we will collaborate with other hospitals using ZOOM.

List of papers published in 2021

Journal

1. Oshima K, Kato K, Ito Y, Daiko H, Nozaki I, Nakagawa S, Shibuya Y, Kojima T, Toh Y, Okada M, Hironaka S, Akiyama Y, Komatsu Y, Maejima K, Nakagawa H, Onuki R, Nagai M, Kato M, Kanato K, Kuchiba A, Nakamura K, Kitagawa Y. Prognostic biomarker study in patients with clinical stage I esophageal squamous cell carcinoma: JCOG0502-A1. Cancer science, 113:1018-1027, 2022

2. Takemura C, Kashima J, Hashimoto T, Ichikawa H, Honma Y, Goto Y, Watanabe SI, Yatabe Y. A mimic of lung adenocarcinoma: a case report of histological conversion of metastatic thyroid papillary carcinoma. Histopathology, 80:1004-1007, 2022

3. Ikeda G, Yamamoto S, Kato K. The safety of current treatment options for advanced esophageal cancer after first-line chemotherapy. Expert opinion on drug safety, 21:55-65, 2022

4. Muro K, Kojima T, Moriwaki T, Kato K, Nagashima F, Kawakami H, Ishihara R, Ogata T, Satoh T, Iwakami K, Han S, Yatsuzuka N, Takami T, Bhagia P, Doi T. Second-line pembrolizumab versus chemotherapy in Japanese patients with advanced esophageal cancer: subgroup analysis from KEYNOTE-181. Esophagus: official journal of the Japan Esophageal Society, 19:137-145, 2022

5. Shibayama T, Shimoi T, Mori T, Noguchi E, Honma Y, Hijioka S, Yoshida M, Ogawa C, Yonemori K, Yatabe Y, Yoshida A. Cytokeratin-positive Malignant Tumor in the Abdomen With EWSR1/FUS-CREB Fusion: A Clinicopathologic Study of 8 Cases. The American journal of surgical pathology, 46:134-146, 2022

6. Mori Y, Kikuchi O, Horimatsu T, Hara H, Hironaka S, Kojima T, Kato K, Tsushima T, Ishihara R, Mukai K, Uozumi R, Tada H, Kasai H, Kawaguchi A, Muto M. Multicenter phase II study of trifluridine/tipiracil for esophageal squamous carcinoma refractory/intolerant to 5-fluorouracil, platinum compounds, and taxanes: the ECTAS study. Esophagus: official journal of the Japan Esophageal Society, 19:444-451, 2022

7. Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. The New England journal of medicine, 386:449-462, 2022

8. Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. The Lancet. Oncology, 23:234-247, 2022

9. Kato K, Ito Y, Nozaki I, Daiko H, Kojima T, Yano M, Ueno M, Nakagawa S, Takagi M, Tsunoda S, Abe T, Nakamura T, Okada M, Toh Y, Shibuya Y, Yamamoto S, Katayama H, Nakamura K, Kitagawa Y. Parallel-Group Controlled Trial of Surgery Versus Chemoradiotherapy in Patients With Stage I Esophageal Squamous Cell Carcinoma. Gastroenterology, 161:1878-1886.e2, 2021

10. Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Nishiyama T, Chen LT, Kang YK. Nivolumab in previously treated advanced gastric cancer (ATTRACTION-2): 3-year update and outcome of treatment beyond progression with nivolumab. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:946-958, 2021

11. Takamizawa S, Honma Y, Murakami N, Mori T, Oka H, Yamamoto S, Kashihara T, Ito K, Kubo Y, Ikeda A, Matsumoto F, Omura G, Kobayashi K, Itami J, Kato K, Yoshimoto S. Short-term outcomes of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) in locally advanced nasopharyngeal carcinoma. Investigational new drugs, 39:564-570, 2021

12. Shah MA, Bennouna J, Doi T, Shen L, Kato K, Adenis A, Mamon HJ, Moehler M, Fu X, Cho BC, Bordia S, Bhagia P, Shih CS, Desai A, Enzinger P. KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. Future oncology (London, England), 17:1143-1153, 2021

13.  Ota Y, Noguchi T, Ariji E, Fushimi C, Fuwa N, Harada H, Hayashi T, Hayashi R, Honma Y, Miura M, Mori T, Nagatsuka H, Okura M, Ueda M, Uzawa N, Yagihara K, Yagishita H, Yamashiro M, Yanamoto S, Kirita T. General rules for clinical and pathological studies on oral cancer (2nd edition): a synopsis. International journal of clinical oncology, 26:623-635, 2021

14. Kashihara T, Nakamura S, Murakami N, Ito K, Matsumoto Y, Kobayashi K, Omura G, Mori T, Honma Y, Kubo Y, Okamoto H, Takahashi K, Inaba K, Okuma K, Igaki H, Nakayama Y, Kato K, Matsumoto F, Yoshimoto S, Itami J. Initial Experience of Intentional Internal High-Dose Policy Volumetric Modulated Arc Therapy of Neck Lymph Node Metastases ≥ 2 cm in Patients With Head and Neck Squamous Cell Carcinoma. Frontiers in oncology, 11:651409, 2021

15. Mikuni H, Yamamoto S, Kato K. Nivolumab for the treatment of esophageal cancer. Expert opinion on biological therapy, 21:697-703, 2021

16. Kosaka M, Honma Y, Ishiki H. Unresolved questions regarding the promise of the TPEx regimen. The Lancet. Oncology, 22:e227, 2021

17. Wada Y, Shimada M, Murano T, Takamaru H, Morine Y, Ikemoto T, Saito Y, Balaguer F, Bujanda L, Pellise M, Kato K, Saito Y, Ikematsu H, Goel A. A Liquid Biopsy Assay for Noninvasive Identification of Lymph Node Metastases in T1 Colorectal Cancer. Gastroenterology, 161:151-162.e1, 2021

18. Yamamoto S, Nagashima K, Kawakami T, Mitani S, Komoda M, Tsuji Y, Izawa N, Kawakami K, Yamamoto Y, Makiyama A, Yamazaki K, Masuishi T, Esaki T, Nakajima TE, Okuda H, Moriwaki T, Boku N. Second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab for patients with metastatic colorectal cancer. BMC cancer, 21:1159, 2021

19. Satoh T, Kato K, Ura T, Hamamoto Y, Kojima T, Tsushima T, Hironaka S, Hara H, Iwasa S, Muro K, Yasui H, Minashi K, Yamaguchi K, Ohtsu A, Doki Y, Matsumura Y, Kitagawa Y. Five-year follow-up of nivolumab treatment in Japanese patients with esophageal squamous-cell carcinoma (ATTRACTION-1/ONO-4538-07). Esophagus: official journal of the Japan Esophageal Society, 18:835-843, 2021

20. Hirose T, Yamamoto S, Kato K. Emerging data on nivolumab for esophageal squamous cell carcinoma. Expert review of gastroenterology & hepatology, 15:845-854, 2021

21. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, Cho BC, Mansoor W, Li SH, Sunpaweravong P, Maqueda MA, Goekkurt E, Hara H, Antunes L, Fountzilas C, Tsuji A, Oliden VC, Liu Q, Shah S, Bhagia P, Kato K. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet (London, England), 398:759-771, 2021

22. Nakamura Y, Okamoto W, Kato T, Esaki T, Kato K, Komatsu Y, Yuki S, Masuishi T, Nishina T, Ebi H, Sawada K, Taniguchi H, Fuse N, Nomura S, Fukui M, Matsuda S, Sakamoto Y, Uchigata H, Kitajima K, Kuramoto N, Asakawa T, Olsen S, Odegaard JI, Sato A, Fujii S, Ohtsu A, Yoshino T. Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nature medicine, 27:1899-1903, 2021

23. Ishikawa M, Takashima A, Nagata Y, Sawada R, Aoki M, Imazeki H, Hirano H, Shoji H, Honma Y, Iwasa S, Okita N, Kato K, Saruta M, Boku N. Tumor growth rate during re-challenge chemotherapy with previously used agents as salvage treatment for metastatic colorectal cancer: A retrospective study. PloS one, 16:e0257551, 2021

24. Miyamoto T, Kato K. Immunotherapy for esophageal carcinoma: a narrative review. Shanghai Chest, 5:2021

25. Ego M, Abe S, Nakatani Y, Nonaka S, Suzuki H, Yoshinaga S, Oda I, Kato K, Honma Y, Itami J, Daiko H, Saito Y, Boku N. Long-term outcomes of patients with recurrent squamous cell carcinoma of the esophagus undergoing salvage endoscopic resection after definitive chemoradiotherapy. Surgical endoscopy, 35:1766-1776, 2021

26. Yagishita S, Kato K, Takahashi M, Imai T, Yatabe Y, Kuwata T, Suzuki M, Ochiai A, Ohtsu A, Shimada K, Nishida T, Hamada A, Mano H. Characterization of the large-scale Japanese patient-derived xenograft (J-PDX) library. Cancer science, 112:2454-2466, 2021

27. Abe S, Matsuzaki J, Sudo K, Oda I, Katai H, Kato K, Takizawa S, Sakamoto H, Takeshita F, Niida S, Saito Y, Ochiya T. A novel combination of serum microRNAs for the detection of early gastric cancer. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:835-843, 2021

28. Ito T, Fujimori N, Honma Y, Kudo A, Hijioka S, Katsushima S, Kimura Y, Fukutomi A, Hisamatsu S, Nakajima A, Shimatsu A. Long-term safety and efficacy of lanreotide autogel in Japanese patients with neuroendocrine tumors: Final results of a phase II open-label extension study. Asia-Pacific journal of clinical oncology, 17:e153-e161, 2021