Department of Gastrointestinal Medical Oncology
Narikazu Boku, Tetsuya Hamaguchi, Ken Kato, Satoru Iwasa, Yoshitaka Honma, Atsuo Takashima, Natsuko Okita, Naoki Takahashi, Yusuke Sasaki, Shoko Nakamura
The Gastrointestinal Medical Oncology Division focuses on the development of new drugs and establishment of standard chemotherapy regimens including multi-modality treatment with surgery and/or radiotherapy for advanced esophageal/ gastric/colorectal cancers, gastrointestinal stromal tumor and other gastrointestinal (GI) malignancies. From this year, we have started to handle induction chemotherapy or palliative chemotherapy for head and neck cancer.
Over recent years, a new generation of molecular-target agents has been developed for colorectal cancer, and bevacizumab (BV) directs against vascular endothelial growth factor (VEGF) and changes the microenvironment of the tumor by inhibiting angiogenesis. Two other molecular target-based drugs are the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab, which were approved in 2008 and 2010. Thereafter, for colorectal cancer, the multikinase inhibitor regorafenib was approved in 2013, and a new cytotoxic agent, TAS-102 (TPI/ FTD), was also approved in March 2014. For gastric cancer, an anti-HER2 monoclonal antibody, trastuzumab, was approved in 2011. And new anti-VEGF agent, ramucirumab, was also approved in March 2015 for gastric cancer based on the results of two randomized controlled trials. Moreover, in recent years, the efficacy of the immune-checkpoint inhibitor has also been evaluated for GI malignancies.
In the near future, we expect to develop other novel agents for the treatment of metastatic GI cancers that inhibit intracellular signal transduction and cellular interactions. However, many unusual adverse effects and a marked increase in medical costs have led to extensive discussion on more accurate targeting of the population using biomarkers. Although the response rates of monotherapy with these molecular-targeted drugs up to now have not been so high (about 5% to 20%) when used broadly in non-selected patients, there are a few new candidate biomarkers that may be useful for identifying patients for whom these molecular-targeted drugs will be remarkably beneficial. For example, all RAS mutation in tumor tissue is one of the negative predictive factors in the response to cetuximab/panitumumab. Accordingly, the identification of molecular markers that can be used to predict tumor shrinkage and/or prolong prognosis will be critical for further progress in the treatment of GI malignancies.
The staff of the GI Medical Oncology Division consist of seven medical oncologists, three chief residents, and three or four residents. We have a daily case conference together at 5 pm and also have a weekly research conference for sharing and discussing the progress of clinical trials or translational research with each other. Intergroup meetings with each surgical division (Colorectal, Gastric, and Esophageal Surgery Divisions) and the Radiation Oncology Division are held weekly to decide optimal treatment strategies for each individual case and to discuss treatment consensus for the disease. Palliative care considering the physical and psychological aspects of each case is another important issue discussed in staff meetings. The palliative care team and psycho-oncologists advise us on how to minimize patient discomfort and anxiety throughout end-of-life care. In 2015, we treated 1,946 hospitalized patients (649 of whom were newly diagnosed). Of these patients, 90 were enrolled into protocol studies.
An endoscopic biopsy and blood sampling before and after chemotherapy provide an excellent opportunity to study biomarkers related to therapy-induced tumor response rates, overall survival, and time to progression or recurrence. We are collecting these fresh samples from patients with gastric cancer to evaluate the correlations between gene expression profiles and patients' outcomes by using genome sequencing, microarray or real time (RT)-PCR techniques.
We have also been measuring the gene expressions of possible predictive biomarkers by using paraffin-embedded GI cancer specimens obtained from surgical resection or endoscopic biopsy, and investigated the correlation between several candidates of related to anti-cancer drug metabolism and clinical outcomes with an RT-PCR assay. Some of these results on the correlation between gene mutation profile and cancer outcomes led to the clinical development of novel molecular targeted drugs, for example, an anti-FGF (fibroblast growth factor) antibody or FGF kinase inhibitor for gastric cancer.
These studies are being performed in collaboration with the Center for Medical Genomics, National Cancer Center Research Institute, or other institutions.
We carried out several clinical trials in collaboration with the Surgery and Radiation Oncology Divisions in our hospital and other institutions. Details of clinical trials are summarized in the Table, including JCOG (Japan Clinical Oncology Group) trials, company initiated and investigator initiated registration trials and other collaborative investigator initiated trials.
Colorectal and Anal Canal Cancer
In first-line treatment, the phase III PARADIGM trial, comparing FOLFOX/panitumumab with FOLFOX/BV in all RAS-wild-type population, is ongoing. We are also investigating whether SIRB regimen is non-inferior to XELOX (capecitabine/ oxaliplatin) plus BV in a multicenter phase III trial (TRICOLORE), and finished patient accrual on schedule. A randomized trial to investigate the superiority of fluoropyrimidine/oxaliplatin/BV to fluoropyrimidine/BV targeted at frail or elderly patients is also ongoing (JCOG1018).
In second-line treatment, we are investigating the non-inferiority of XELIRI (capecitabine/ irinotecan) to FOLFIRI (5-FU/l-LV/irinotecan), for patients whose first-line treatment with FOLFOX or XELOX plus BV failed, in a multicenter phase III trial conducted in Asian countries (AXEPT), and finished patient accrual on schedule.
As an adjuvant treatment, JCOG0910, comparing S-1 with capecitabine, finished patient recruitment in 2013 on schedule, and the result was shown in ASCO 2015. Unfortunately, it could not show the non-inferiority of S-1 to capecitabine in terms of relapse free survival. A randomized trial comparing adjuvant mFOLFOX6 with observations after complete resection of liver metastasis from colorectal cancer is ongoing (JCOG0603).
The phase II part of JCOG0903, a phase I/ II trial of definitive chemoradiotherapy with S-1/ MMC for locally advanced anal canal squamous cell carcinoma finished patient accrual on schedule.
In first-line treatment, a pivotal phase III trial comparing S-1/CDDP (CS) to S-1/CDDP/Docetaxel (DCS), patient enrollment was finished in March 2016. A new phase III trial comparing TAS-118 (S-1 plus l-LV)/oxaliplatin with CS has started from 2015. And a phase II/III study, comparing FLTAX with 5FU alone for patients who are inappropriate for CDDP usage or oral administration of S-1 due to severe peritoneal dissemination is also ongoing.
In second-line treatment, molecular-targeted drugs for advanced gastric cancer have been investigated. For HER2 negative gastric cancer, a phase III trial which will evaluate the additive effect of nimotuzumab, anti-EGFR antibodies, combined with irinotecan in second-line chemotherapy (ENRICH) is ongoing and is targeted at patients with high expression of EGFR. Two phase III trials which evaluate the additive effect of (i) Olaparib (PARP inhibitor), (ii) BBI608 (an inhibitor targeted at cancer stem cell), combined with paclitaxel finished patient accrual. Moreover, regarding the cases inappropriate to the ENRICH trial, a feasibility study for a combination of weekly abraxane with ramcirumab started from the end of 2015.
For HER2 positive gastric cancer, a phase III trial which evaluates the additive effect of pertuzumab with capecitabine and cisplatin plus trastuzumab in first-line treatment (JACOB) finished patient accrual. A multi-center feasibility study of S-1/oxaliplatin plus trastuzumab in first-line treatment started from early 2015. A result of the phase II/III trial comparing TDM-1, ado-trastuzumab emtansine, with paclitaxel in second-line treatment (GATSBY) was reported to fail in showing superiority to paclitaxel at the ASCO-GI 2016 meeting. And a phase III trial comparing MK-3475, anti-programed cell death 1 (PD-1) immune-checkpoint inhibitor antibody, with weekly paclitaxel (KEYNOTE-061) is also ongoing.
In salvage-line treatment, a randomized trial to investigate the efficacy of ONO-4538, anti-PD-1 immune-checkpoint inhibitor antibody, compared with best supportive care (BSC) has completed patient recruitment.
Based on the results of JCOG9907 trial, in Japan, the standard care for stage IB/II/III esophageal cancer is preoperative 5-FU plus CDDP (CF) followed by surgery. The large pivotal trial JCOG1109, which compared DCF (Docetaxel plus CF) or CF plus radiotherapy (CF-RT, 41.4Gy) regimen with standard preoperative CF in stage IB/II/III esophageal cancer, started from 2012, and is progressing on schedule. A phase II study, JCOG0909 on the efficacy of CF-RT (50.4 Gy) regimen followed by salvage surgery or endoscopic resection in stage IB/II/III esophageal cancer, finished accrual in 2014.
In first-line treatment, a phase I/II study, JCOG0807 demonstrated the promising efficacy and feasibility of bi-weekly DCF regimen. According to this precedent study, a phase III trial comparing biweekly DCF with standard CF regimen started from September 2014 in JCOG.
In second-line treatment, two randomized controlled trials to investigate the efficacy of PD-1 immune-checkpoint inhibitor are ongoing; (i) Taxan versus ONO-4538 (OPERA) and (ii) paclitaxel versus MK-3475 (KEYNOTE-181).
In salvage-line treatment, two phase II studies (i) ONO-4538, and (ii) Sym004, a mixture of two synergistic full-length anti-EGFR antibodies, which bind to two separate non-overlapping epitopes on EGFR, finished patient accrual. A feasibility study to investigate the efficacy of MK-3475 is now ongoing. A multi-center feasibility study of TAS-102 has been also started.
For metastatic neuroendocrine carcinoma (NEC) in GI-tract or hepato-billiary-Pancreatic field, a phase III trial comparing irinotecan plus CDDP with etoposide plus CDDP as first-line treatment (JCOG1213) is progressing faster than expected. And for metastatic head and neck squamous cell carcinoma, a phase III trial comparing MEDI-4736 (PD-L1 antibody) /Tremelimumab (anti-CTLA-4 antibody), MEDI-4736, and standard chemotherapy (Docetaxel or Cetuximab or S-1) in second-line treatment (EAGLE) is also ongoing, collaborating with doctors in the Department of Head and Neck Oncology. Several clinical trials have also been conducted and eligible patients have been enrolled as shown in the Table.
List of papers published in 2015
- Takahashi T, Yamahsita S, Matsuda Y, Kishino T, Nakajima T, Kushima R, Kato K, Igaki H, Tachimori Y, Osugi H, Nagino M, Ushijima T. ZNF695 methylation predicts a response of esophageal squamous cell carcinoma to definitive chemoradiotherapy. J Cancer Res Clin Oncol, 141:453-463, 2015
- Utsumi H, Honma Y, Nagashima K, Iwasa S, Takashima A, Kato K, Hamaguchi T, Yamada Y, Shimada Y, Kishi Y, Nara S, Esaki M, Shimada K. Bevacizumab and postoperative wound complications in patients with liver metastases of colorectal cancer. Anticancer Res, 35:2255-2261, 2015
- Chua C, Tan IB, Yamada Y, Rha SY, Yong WP, Ong WS, Tham CK, Ng M, Tai DW, Iwasa S, Lim HY, Choo SP. Phase II study of trastuzumab in combination with S-1 and cisplatin in the first-line treatment of human epidermal growth factor receptor HER2-positive advanced gastric cancer. Cancer Chemother Pharmacol, 76:397-408, 2015
- Iwasa S, Nagashima K, Yamaguchi T, Matsumoto H, Ichikawa Y, Goto A, Yasui H, Kato K, Okita NT, Shimada Y, Yamada Y. S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: a pooled analysis of four phase II studies. Cancer Chemother Pharmacol, 76:605-614, 2015
- Iwasa S, Souda H, Yamazaki K, Takahari D, Miyamoto Y, Takii Y, Ikeda S, Hamaguchi T, Kanemitsu Y, Shimada Y. Safety and efficacy of adjuvant therapy with oxaliplatin, leucovorin and 5-fluorouracil after mesorectal excision with lateral pelvic lymph node dissection for stage iii lower rectal cancer. Anticancer Res, 35:1815-1819, 2015
- Nagashima K, Iwasa S, Yanai T, Hashimoto H, Suzuki K, Ohyanagi F, Shimada Y, Yamamoto N. A double-blind randomized Phase II study of olanzapine 10 mg versus 5 mg for emesis induced by highly emetogenic chemotherapy. Jpn J Clin Oncol, 45:229-231, 2015
- Yoshino T, Komatsu Y, Yamada Y, Yamazaki K, Tsuji A, Ura T, Grothey A, Van Cutsem E, Wagner A, Cihon F, Hamada Y, Ohtsu A. Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations. Invest New Drugs, 33:740-750, 2015
- Shoji H, Yamada Y, Okita N, Takashima A, Honma Y, Iwasa S, Kato K, Hamaguchi T, Shimada Y. Amplification of FGFR2 Gene in Patients with Advanced Gastric Cancer Receiving Chemotherapy: Prevalence and Prognostic Significance. Anticancer Res, 35:5055-5061, 2015
- Takahashi N, Yamada Y, Furuta K, Nagashima K, Kubo A, Sasaki Y, Shoji H, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Hamaguchi T, Shimada Y. Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer. Cancer Sci, 106:604-610, 2015
- Tanaka Y, Aoyagi K, Minashi K, Komatsuzaki R, Komatsu M, Chiwaki F, Tamaoki M, Nishimura T, Takahashi N, Oda I, Tachimori Y, Arao T, Nishio K, Kitano S, Narumi K, Aoki K, Fujii S, Ochiai A, Yoshida T, Muto M, Yamada Y, Sasaki H. Discovery of a Good Responder Subtype of Esophageal Squamous Cell Carcinoma with Cytotoxic T-Lymphocyte Signatures Activated by Chemoradiotherapy. PLoS One, 10:e0143804, 2015
- Yamazaki K, Kuwano H, Ojima H, Otsuji T, Kato T, Shimada K, Hyodo I, Nishina T, Shirao K, Esaki T, Ohishi T, Denda T, Takeuchi M, Boku N. A randomized phase II study of combination therapy with S-1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer. Cancer Chemother Pharmacol, 75:569-577, 2015
- Ioka T, Okusaka T, Ohkawa S, Boku N, Sawaki A, Fujii Y, Kamei Y, Takahashi S, Namazu K, Umeyama Y, Bycott P, Furuse J. Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial. Jpn J Clin Oncol, 45:439-448, 2015
- Nozaki I, Kato K, Igaki H, Ito Y, Daiko H, Yano M, Udagawa H, Mizusawa J, Katayama H, Nakamura K, Kitagawa Y. Evaluation of safety profile of thoracoscopic esophagectomy for T1bN0M0 cancer using data from JCOG0502: a prospective multicenter study. Surg Endosc, 29:3519-3526, 2015
- Fujiwara Y, Yonemori K, Shibata T, Okita N, Ushirozawa N. Japanese universal health care faces a crisis in cancer treatment. Lancet Oncol, 16:251-252, 2015
- Watanabe T, Itabashi M, Shimada Y, Tanaka S, Ito Y, Ajioka Y, Hamaguchi T, Hyodo I, Igarashi M, Ishida H, Ishihara S, Ishiguro M, Kanemitsu Y, Kokudo N, Muro K, Ochiai A, Oguchi M, Ohkura Y, Saito Y, Sakai Y, Ueno H, Yoshino T, Boku N, Fujimori T, Koinuma N, Morita T, Nishimura G, Sakata Y, Takahashi K, Tsuruta O, Yamaguchi T, Yoshida M, Yamaguchi N, Kotake K, Sugihara K, Japanese Society for Cancer of the Colon and Rectum. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin Oncol, 20:207-239, 2015
- Yokota T, Ando N, Igaki H, Shinoda M, Kato K, Mizusawa J, Katayama H, Nakamura K, Fukuda H, Kitagawa Y. Prognostic Factors in Patients Receiving Neoadjuvant 5-Fluorouracil plus Cisplatin for Advanced Esophageal Cancer (JCOG9907). Oncology, 89:143-151, 2015
- Shinoda M, Ando N, Kato K, Ishikura S, Kato H, Tsubosa Y, Minashi K, Okabe H, Kimura Y, Kawano T, Kosugi S, Toh Y, Nakamura K, Fukuda H, Japan Clinical Oncology Group. Randomized study of low-dose versus standard-dose chemoradiotherapy for unresectable esophageal squamous cell carcinoma (JCOG0303). Cancer Sci, 106:407-412, 2015
- Kataoka K, Nakamura K, Mizusawa J, Fukuda H, Igaki H, Ozawa S, Hayashi K, Kato K, Kitagawa Y, Ando N. Variations in survival and perioperative complications between hospitals based on data from two phase III clinical trials for oesophageal cancer. Br J Surg, 102:1088-1096, 2015
- Osawa M, Kudoh S, Sakai F, Endo M, Hamaguchi T, Ogino Y, Yoneoka M, Sakaguchi M, Nishimoto H, Gemma A. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. Int J Clin Oncol, 20:1063-1071, 2015
- Kataoka K, Tsushima T, Mizusawa J, Hironaka S, Tsubosa Y, Kii T, Shibuya Y, Chin K, Katayama H, Kato K, Fukuda H, Kitagawa Y, Japan Esophageal Oncology Group/Japan Clinical Oncology Group. A randomized controlled Phase III trial comparing 2-weekly docetaxel combined with cisplatin plus fluorouracil (2-weekly DCF) with cisplatin plus fluorouracil (CF) in patients with metastatic or recurrent esophageal cancer: rationale, design and methods of Japan Clinical Oncology Group study JCOG1314 (MIRACLE study). Jpn J Clin Oncol, 45:494-498, 2015
- Mizukami T, Togashi Y, Sogabe S, Banno E, Terashima M, De Velasco MA, Sakai K, Fujita Y, Tomida S, Nakajima TE, Boku N, Nishio K. EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition. Int J Oncol, 47:499-505, 2015
- Horie Y, Yamazaki K, Funakoshi T, Hamauchi S, Taniguchi H, Tsushima T, Todaka A, Machida N, Taku K, Fukutomi A, Onozawa Y, Yasui H, Mizukami T, Izawa N, Hirakawa M, Tsuda T, Nakajima T, Boku N. Predictability of antitumor efficacy of cetuximab plus irinotecan based on skin rash severity according to observation period in patients with metastatic colorectal cancer following failure of fluorouracil, irinotecan and oxaliplatin. Mol Clin Oncol, 3:1029-1034, 2015
- Feilchenfeldt J, Varga Z, Siano M, Grabsch HI, Held U, Schuknecht B, Trip A, Hamaguchi T, Gut P, Balague O, Khanfir K, Diebold J, Jochum W, Shoji H, Kushima R, Wagner D, Shimada Y, Cats A, Knuth A, Moch H, Aebi S, Hofer S. Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2). Br J Cancer, 113:716-721, 2015
- Doi T, Yoshino T, Fuse N, Boku N, Yamazaki K, Koizumi W, Shimada K, Takinishi Y, Ohtsu A. Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer. Invest New Drugs, 33:1068-1077, 2015
- Nishina T, Kato T, Yamazaki K, Yoshino T, Miyata Y, Esaki T, Moriwaki T, Boku N, Hyodo I. A phase II study of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA) in patients with unresectable metastatic colorectal cancer. Cancer Chemother Pharmacol, 76:547-553, 2015
- Ryu MH, Baba E, Lee KH, Park YI, Boku N, Hyodo I, Nam BH, Esaki T, Yoo C, Ryoo BY, Song EK, Cho SH, Kang WK, Yang SH, Zang DY, Shin DB, Park SR, Shinozaki K, Takano T, Kang YK, SOS study investigators. Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS). Ann Oncol, 26:2097-2101, 2015
- Tahara M, Fuse N, Mizusawa J, Sato A, Nihei K, Kanato K, Kato K, Yamazaki K, Muro K, Takaishi H, Boku N, Ohtsu A. Phase I/II trial of chemoradiotherapy with concurrent S-1 and cisplatin for clinical stage II/III esophageal carcinoma (JCOG 0604). Cancer Sci, 106:1414-1420, 2015
- Kataoka K, Tokunaga M, Mizusawa J, Machida N, Katayama H, Shitara K, Tomita T, Nakamura K, Boku N, Sano T, Terashima M, Sasako M, Stomach Cancer Study Group/Japan Clinical Oncology Group. A randomized Phase II trial of systemic chemotherapy with and without trastuzumab followed by surgery in HER2-positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301 (Trigger Study). Jpn J Clin Oncol, 45:1082-1086, 2015
- Ouchi K, Takahashi S, Yamada Y, Tsuji S, Tatsuno K, Takahashi H, Takahashi N, Takahashi M, Shimodaira H, Aburatani H, Ishioka C. DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer. Cancer Sci, 106:1722-1729, 2015
- Kato K. Chemotherapy and Chemoradiotherapy. In: Ando N (ed), Esophageal Squamous Cell Carcinoma - Diagnosis and Treatment, Japan, Springer Japan, pp 197-225, 2015