Annual Report 2018
Department of Head and Neck Medical Oncology
Narikazu Boku, Yoshitaka Honma
Introduction
The Head and Neck Medical Oncology Division focuses on the development of new drugs and establishment of standard therapy including multi-modality treatment with surgery and/or radiotherapy for advanced head and neck cancer (HNC), which includes many types of malignant diseases arising from the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, nasal/paranasal cavity, salivary gland, ear canal, and thyroid and so on. While main histology of HNC is squamous cell carcinoma (HNSCC), there are various histological types especially in the nasal/paranasal cavity and salivary gland. Therefore, treatment strategy based on pathological findings is very important for advanced HNC not only in clinical practice but also clinical trials.
We are continuously trying to develop novel agents for the treatment of advanced HNC that inhibit intracellular signal transduction, cellular interactions, and immunogenic tolerance. As a result, new effective drugs have been approved for HNC recently. However, many unusual adverse effects and marked increases in medical costs lead to extensive discussion on more accurate predictions using biomarkers for targeting the optimal population. Therefore, the identification of molecular markers to predict tumor shrinkage and/or prognosis in the treatment with molecular target agents and immune checkpoint inhibitors will be critical for the further progress in treatment of HNC. Actually, although the response rate of monotherapy with cetuximab (Cmab) or nivolumab (NIVO) is not so high when used for non-selected patients, expression of programed cell death-ligand 1 (PD-L1) in cancer cells or antigen-presenting cells is a candidate of positive predictive markers for the response to anti-PD-1 antibody.
Routine activities
The staff of the Head and Neck Medical Oncology Division consists of 2 medical oncologists. In 2018, we treated 87 hospitalized patients (67 of whom were newly diagnosed). Of these patients, 11 were enrolled in protocol studies. We hold a daily case conference at 5 pm after finishing routine clinical work and also a weekly research conference with staff of the GI Medical Oncology Division to share and discuss the progress of clinical trials or in-house research. Multidiciplinary meetings with the Head and Neck Surgery Division, the Radiation Oncology Division, the Diagnostic Radiology Division, and the Pathology Division are held weekly to decide optimal treatment strategies for an individual case and to discuss treatment consensus for the disease. Palliative and supportive care for quality of life including physical, psychological and social aspects of each case are also important issues which are performed after discussion with other dedicated medical staff. The palliative care team and psycho-oncologists advise us on the palliative care to minimize patient discomfort and anxiety throughout end-of-life care.
Clinical trials
We are participating in several clinical trials, such as JCOG (Japan Clinical Oncology Group) trials, company sponsored trials, and other collaborative investigator initiated trials, in collaboration with the Head and Neck Surgery Division, the Radiation Oncology Division, and the Pathology Division in our hospital or other institutes. Details of clinical trials are summarized in the Table.
1. Palliative chemotherapy for recurrent/ metastatic HNSCC (RM-HNSCC)
Until the 2000s, only cytotoxic agents were available for advanced HNC, and new drug development did not progress so much for a long time. Recently, there are several new drugs approved for advanced HNC. For 1st- line treatment for advanced HNSCC, a survival benefit by adding cetuximab (anti-epidermal growth factor receptor antibody) to platinumbased chemotherapy was shown in the EXTREME trial, and cetuximab was approved for advanced HNC as 1st-line treatment of advanced HNSCC in 2012. In ESMO 2018, as the KEYNOTE-048 trial showed superiority of pembrolizumab (anti-PD-1 antibody) monotherapy to EXTREME regimen in CPS-positive HNSCC and non-inferiority/ superiority of 5-fluorouracil + platinum + pembrolizumab to EXTREME regimen, pembrolizumab-based regimen will be a standard regimen for HNSCC in the near future. A phase III trial comparing nivolumab plus ipilimumab with EXTREME regimen (CheckMate-651) as 1st - line treatment for metastatic HNSCC has finished patient accrual. For 2nd-line treatment, nivolumab (anti-PD-1 antibody) was approved based on the result of Checkmate-141 for platinum-failure HNC in 2017.
2. Multi-modality treatment for locally advanced HNSCC (LA-HNSCC)
For LA-HNSCC, collaborating with the Department of Head and Neck Surgery and the Department of Radiation Oncology, several clinical trials are ongoing. A phase III trial investigating the additive effect of avelumab (anti-PD-L1 antibody) to definitive CDDP + RT for LA-HNSCC has finished patient accrual. The IMvoke010 trial investigating the additive effect of atezolizumab (anti-PD-L1 antibody) as maintenance therapy after multidisciplinary treatment is ongoing.
3. Palliative chemotherapy for recurrent/ metastatic thyroid cancer
For radio-iodine failure differentiated thyroid cancer (papillary and follicular thyroid cancer), multi-targeted tyrosine kinase inhibitor such as sorafenib and lenvatinib were approved based on the results of phase III trials (DECISION trial and SELECT trial). For medullary thyroid cancer, RET-inhibitor is a first choice because most of them have RET gene mutation. Vandetanib (inhibitor of RET kinase, VEGFR, and EGFR signaling) was approved based on the result of a phase III trial. A phase II trial of LOXO-292, highly selective RET inhibitor, is ongoing collaborating with the Department of Thoracic Oncology. For anaplastic thyroid cancer, no standard treatment has been established. However, lenvatinib showed moderate antitumor activity even for anaplastic thyroid cancer in a domestic phase II trial, so lenvatinib is available for anaplastic thyroid cancer in clinical practice.
Table 1. Clinical trial for new drug development
Research activities
We perform many retrospective studies, not only in our division but also in collaboration with other hospitals, for resolving clinical questions and for making rationale for future clinical trials. A trans-oral/percutaneous biopsy and blood sampling before and after cetuximab and nivolumab can provide an excellent opportunity to study biomarkers related to therapy-induced tumor response, overall survival, and time to progression or recurrence. We are collecting these fresh samples of patients with HNSCC to evaluate the correlations between patients' outcome and biomarkers such as gene expression or immunogenic profiles assessed by genome sequencing, immune-panel, microarray or real time PCR techniques. We are also measuring the gene expressions of possible predictive biomarkers using paraffin-embedded HNC specimens obtained from surgical resection or trans-oral/percutaneous biopsy, and investigated the correlation between clinical outcomes and enzymes related to anti-cancer drug metabolism. These studies are being conducted in collaboration with the Center for Medical Genomics, National Cancer Center Research Institute, or other institutions.