中國醫藥大學機構典藏 China Medical University Repository, Taiwan:Item 310903500/25196

行政院國家科學委員會專題研究計畫 成果報告

口服環氧化酵素第二型抑制劑 celebrex 及注射抗癌藥物

cisplatin 與 5-fluorouracil 對頭頸部鱗狀細胞癌的治療

中 華 民 國 93 年 12 月 24 日

行政院國家科學委員會專題研究計畫成果報告

endothelial growth factor, VEGF) 基因表達的增加。第二期臨 床 試 驗 於 大 直 腸 癌 及 非 小 細 胞 肺 癌 結 果 顯 示 合 併 COX-2 抑 制 劑 celebrex 與 化 療 一 起 使 用 可 增 加 化 療 的 效 果 。 本試驗為開 放 性，非 對 照 性 的 第 二 期 臨 床 試 驗 合 併 celebrex 與 化 療 藥 物 cisplatin 及 5-fluorouracil 一 起 使 用 於 治 療 失 敗 局 部 復 發 或 有 遠 處 轉 移 的 SCCHN 病 人。因 試 驗 期 間 正 逢 SARS 過 後 及 心 臟 副 作 用 發 現 於 COX-2 抑 制 劑 ， 收 案 情 況 不 理 想 ， 只 收 四 人 。 此 四 位 患 者 在 接 受 一 至 二次的療 程 後，皆 因 疾 病 惡 化 而 退 出 。 在三位患者的血 清，化 療 前 後 的 前 列 腺 素 E2 可 維持不 變或減 少 約一 半 ， 但 血 清 VEGF 卻 可 增 加 1.5 至 三 倍 。 我們的初步 結 果 顯 示 celebrex 無 法有效抑制 VEGF 的過度表達於 SCCHN 病人接受 cisplatin 及 5-fluorouracil， 這很可能是四個病人都 治療失敗的原因。 最近報告指出 celebrex 可增加心血管疾病併發症， 因 此我們將修改研究計劃， 使用 VEGF 抑 制 劑 Avastin 合 併 化 療 於 SCCHN 病人。 關 鍵 詞 ： 環 氧 化 酵 素 第 二 型 、 頭 頸 部 鱗 狀 細 胞 癌 、 血 管 內 皮 生 長 激 素 、 化 療 、 前 列 腺 素 E2 Abstract Induction of cyclooxygenase-2 (COX-2) gene expression in squamous cell carcinoma of head and neck (SCCHN) cells results in anti-apoptotic signaling and increased vascular endothelial growth factor (VEGF) expression. Several phase II studies using celecbrex, a selective COX-2 inhibitor, in combination with chemotherapy have shown to increase chemotherapy efficacy in patients with non-small cell lung and colorectal cancers. The purpose of this pilot study is to examine serum VEGF and prostaglandin E2 (PGE2) expression in SCCHN patients receiving celebrex and chemotherapy with an intention to develop a novel therapeutic regimen.

This is an open-label one-arm phase II study with ongoing accrual of recurrent or metastatic SCCHN patients who meet the eligibility criteria are given celecbrex 400mg orally twice a day starting 3 days before first course of chemotherapy and continuing through out study period. Chemotherapy is repeated every 28 days with cisplatin 100 mg/m2 IV infusion 2 hours on day 1, then 5-fluorouracil 1000 mg/m2 IV

infusion 24 hours daily for 5 days. We have a very slow accrual due to post SARS period, and recent cardiac side effect from celebrex reported in the media. Four patients are enrolled into the study and we have analyzed their blood samples for VEGF gene expression and PGE2 levels. One patient’s VEGF gene expression remained unchanged during the first and second cycles of treatment. Three patients’ VEGF gene expression increased 1.5- to 3-fold by the end of first or second cycle. All four patients were found to have progression of disease. Analysis of serum prostaglandin E2 showed adequate COX-2 inhibition in all those patients despite elevated VEGF expression.

In conclusion, celebrex can not effectively suppress induction of VEGF gene expression in SCCHN patients receiving chemotherapy with cisplatin and 5-fluorouracil, and may not enhance chemotherapy efficacy in this setting. Given the recent report of increased cardiac toxicity in patients receiving high-dose celebrex, we are planning to modify our study protocol to use VEGF inhibitor such as Avastin with chemotherapy in SCCHN patients.

Keywords: cyclooxygenase-2, squamous cell carcinoma of head and neck, vascular endothelial growth factor, chemotherapy, prostaglandin E2.

二、緣由與目的

SCCHN is one of the most common malignancies in adults, and accounts for more than 5% of the cancer incidence and more than 1500 deaths annually in Taiwan.

For patients presented with recurrent and metastatic SCCHN, the goals of treatment is no longer the cure but prolonging life and improving quality of life with various cytotoxic regimens that may achieve measurable reduction in tumor and provide palliation. For patients receiving palliative chemotherapy, they have median survival of about 6 months, compared to only 4 months for patients receiving only supportive care. The cytotoxic drugs most commonly used worldwide to treat head and neck cancer are methotrexate, cisplatin, carboplatin,

fluorouracil, gemcitabine, paclitaxel, and docetaxel. In general, 15 to 40 percent of patients have brief responses to these single agents. The combination of cisplatin and fluorouracil given by continuous intravenous infusion is the most commonly used

chemotherapy regimen in Taiwan for patients with locally advanced or recurrent SCCHN, and the response rate for treatment-naïve patients varies between 75% and 85%.

Recent advance in understanding the cancer biology seems to provide an avenue for improving disease control in recurrent and metastatic SCCHN. Molecules selectively or preferentially expressed on tumor cells, such as epidermal growth factor receptor, VEGF and COX-2, are shown to render cellular resistance to

chemotherapeutic agents or radiation in SCCHN. Evidence is rapidly increasing that COX-2 is involved in tumorigenesis,

angiogenesis, metastasis, and resistance to cytotoxic therapy. Increased expression of COX-2 has been shown in a wide variety of solid tumor malignancies including colorectal adenoma and carcinoma, gastric cancer, Barrett's esophagus and associated adenocarcinomas, pancreatic cancer, lung cancer, breast cancer, transitional cell carcinoma of the urinary bladder, and SCCHN.

analyzed in 52 SCCHN patients by assessing tumor COX-2 protein expression and serum PGE2 levels correlated with VEGF

expression, tumor angiogenesis and shorter survival. Induction of COX-2 gene

expression by epidermal growth factor (EGF) and Escherichia coli lipopolysaccharide (LPS) in SCCHN cell lines resulted in an increase in VEGF mRNA and protein production, and celebrex reversed the EGF- and

LPS-dependent COX-2, VEGF, and PGE2 increases. These data indicates a central role of COX-2 pathway in SCCHN angiogenesis by modulating VEGF production and indicates that COX-2 inhibitors such as celebrex may be useful in SCCHN treatment

Celebrex and other selective COX-2 inhibitors have been safely and effectively combined with chemotherapeutic agents in human clinical trials including colon and lung cancers. Altorki et al. have reported that in non-small cell lung cancer patients

underwent six weeks of chemotherapy with standard doses of paclitaxel and carboplatin plus celebrex 400 mg twice a day orally until the day before surgical resection, one-third of the patients showed at least 95 percent of tumor necrosis. It also has been shown that celebrex may decrease certain toxicities from chemotherapy such as neutropenia, diarrhea and hand-foot syndrome. Ongoing clinical trials are currently assessing the potential therapeutic role of selective COX-2

inhibitors in both prevention and treatment of a diverse range of human cancers. Given there is no current trial in the treatment SCCHN incorporating selective COX-2 inhibitor, we would like to conduct a pilot study to test whether combination of celebrex and chemotherapy will improve treatment efficacy in locally recurrent and metastatic SCCHN.

Our objective is to improve clinical cancer therapy by developing a novel therapeutic strategy in the treatment of SCCHN, which utilizes celebrex, a selective COX-2 inhibitor, to enhance chemotherapy activity. We have conducted an open-label one-arm phase II study with ongoing accrual. Recurrent or metastatic SCCHN patients who meet the eligibility criteria are given

celecoxib 400mg po bid starting 3 days before first course of chemotherapy and continuing through out study period.

Chemotherapy is repeated every 28 days with cisplatin 100 mg/m2 IV infusion 2 hours on day 1, then 5-fluorouracil 1000 mg/m2 IV infusion 24 hours daily for 5 days. Evaluation of treatment response is conducted after 2 cycles of

chemotherapy. Twenty ml blood sample and 24-hour urine are collected on 4

days prior to 1st cycle of chemotherapy (before taking celecoxib), day 1 and day 5 of each chemotherapy cycle, and are subject to VEGF and PGE2 measurement by enzyme immunoassay kits from Amersham. Additionally, peripheral blood mononuclear cells are used for VEGF RT-PCR.

三、結果與討論

We have analyzed the first 4 patients' blood samples for VEGF gene

expression. One patient's VEGF gene expression remained unchanged during the first and second cycles of treatment (patient B). Three patients' VEGF gene expression increased 1.5- to 3-fold by the end of first to second cycle. Analysis of serum

prostaglandin E2 showed adequate COX-2 inhibition by celebrex (see attached table) All four patients enrolled into the study were found to have progression of disease after one to two cycles of treatment. There was no grade III/IV hematological toxicities, or treatment-related mortality.

Celebrex can not effectively suppress induction of VEGF gene

expression in SCCHN patients receiving chemotherapy with cisplatin and

5-fluorouracil, and may not enhance chemotherapy efficacy in this setting. Future study using celecoxib and VEGF inhibitor in combination with

Serum VEGF (pg/ml) Serum PGE2 (pg/ml) Patient A -D4 496.4 267.8 Patient A C1D1 1262.2 543.1 Patient A C1D5 1067.0 351.5 Patient B -D4 2889.2 505.6 Patient B C1D1 2976.4 427.0 Patient B C1D5 2950.3 365.6 Patient B C2D1 2434.2 472.3 Patient B C2D5 2793.1 772.4 Patient C -D4 425.9 611.7 Patient C C1D1 227.6 375.0 Patient C C1D5 633.1 342.0 Patient C C2D1 1379.2 272.1 Patient C C2D5 1212.0 312.9 Patient D -D4 497.4 129.6 Patient D C1D1 448.5 155.1 Patient D C1D5 123.2 239.2 Patient D C2D1 129.3 67.4 Patient D C2D5 672.0 84.8

-D4: 3 days prior to first cycle of chemotherapy

C1D1: cycle 1 day1, etc.

四、計畫成果自評

We will present the preliminary results in 2005 annual meeting of American Society of Clinical Oncology. In order to conclude this study, we will need to recruit more patients. However due to recent media report of unnecessary cardiovascular side effects of celebrex. It will be very difficult to enroll any more patient into this study. We plan to modify our study to incorporate Avastin, a monoclonal antibody against VEGF into the treatment regimen. We are expecting at least 1 SCI-grade publications from this project.

五、參考文獻

(1) Department of Health, the Executive Yuan, R.O.C. Cause of Death Statistics in Taiwan Area, 2001. 2002..

(2) Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med.

2001;345:1890-1900.

(3) Lamont EB, Vokes EE. Chemotherapy in the management of squamous-cell carcinoma of the head and neck. Lancet Oncol. 2001;2:261-69.

(4) Khuri FR, Shin DM, Glisson BS, Lippman SM, Hong WK. Treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck: current status and future directions. Semin Oncol. 2000;27:25-33.

(5) Lin DT, Subbaramaiah K, Shah JP, Dannenberg AJ, Boyle JO. Cyclooxygenase-2: a novel molecular target for the prevention and treatment of head and

neck cancer. Head Neck. 2002;24:792-99. 999;59:991-94.

(6) Renkonen J, Wolff H, Paavonen T. Expression of cyclooxygenase-2 in human tongue carcinoma and its precursor lesions. Virchows Arch. 2002;440:594-97. (7) Banerjee AG, Gopalakrishnan VK, Bhattacharya I, Vishwanatha JK. Deregulated cyclooxygenase-2 expression in oral premalignant tissues. Mol Cancer Ther. 2002;1:1265-71.

(8) Yoshimatsu K, Altorki NK, Golijanin D, Zhang F, Jakobsson PJ, Dannenberg AJ et al. Inducible

prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin Cancer Res. 2001;7:2669-74.

(9) Gallo O, Masini E, Bianchi B, Bruschini L, Paglierani M, Franchi A. Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma. Hum Pathol. 2002;33:708-14.

(10) Gallo O, Franchi A, Magnelli L, Sardi I, Vannacci A, Boddi V et al. Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia. 2001;3:53-61.

(11) Nishimura G, Yanoma S, Mizuno H, Kawakami K, Tsukuda M. A selective cyclooxygenase-2 inhibitor suppresses tumor growth in nude mouse xenografted with human head and neck squamous carcinoma cells. Jpn J Cancer Res. 1999;90:1152-62. (12) Zweifel BS, Davis TW, Ornberg RL, Masferrer JL. Direct evidence for a role of cyclooxygenase 2-derived prostaglandin E2 in human head and neck xenograft tumors. Cancer Res. 2002;62:6706-11. (13) Sweeney C et al. A phase II trial of irinotecan, 5-fluorouracil, leucovorin, celecoxib and glutamine as first line therapy for advanced colorectal cancer: a Hoosier Oncology Group study. Proc Am Soc Clin Oncol. 2002;21:2235a.

(14) Blanke CD et al. A phase II trial of celecoxib, irinotecan, 5-fluorouracil, and leucovorin in patients

with unresectable or metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2002;21:505a.

(15) Becerra CR et al. A phase II study of

5-fluorouracil and leucovorin calcium plus open-label Rofecoxib in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2002;21:2240a. (16) Csiki C et al. Cyclooxygenase-2 inhibition + docetaxel in recurrent non-small cell lung cancer: preliminary results of a phase II trial (THO-0054). Proc Am Soc Clin Oncol. 2002;21:1187a.

(17) Altorki NK et al. Celecoxib, a selective COX-2 inhibitor, enhances the response to preoperative paclitaxel/carboplatin in early stage non-small cell lung cancer. J Clin Oncol. 2003;21:2645-50.