日本研究：S-1辅助化疗可改善胰腺癌生存

旧金山——一项仍在进行中的Ⅲ期临床试验的中期分析结果显示，接受手术的日本胰腺癌患者如果在术后使用化疗药S-1，则在2年内死亡的风险比接受吉西他滨者减少44%。

S-1在美国尚未获准上市，但在日本已被允许使用，用于治疗胰腺癌和若干种其他癌症。

Katsuhiko Uesaka博士

日本静冈癌症中心医院的Katsuhiko Uesaka博士及其同事在美国临床肿瘤学会胃肠肿瘤(ASCO GI)研讨会上报告，共有385例胰腺癌患者被随机分组，接受术后S-1或吉西他滨辅助化疗。在发生205例死亡之后按计划进行了中期分析，结果显示S-1组187例患者中有70%在2年时仍健在，而吉西他滨组中仅有53%仍存活。

S-1组患者的复发风险也更低。2年时，S-1组有49%未出现疾病进展，而吉西他滨组仅有29%无进展。至疾病进展的中位时间，S-1组和吉西他滨组分别为23个月和11个月。

本项研究仍在进行中，最终分析将在发生240例死亡时进行。

S-1是一种口服氟嘧啶，由替加氟、吉美拉西和氧嗪酸组成。该药已在欧洲获准用于治疗胃癌，但使用剂量小于日本的批准剂量，原因是该药在白人患者中更易引起腹泻。

这项日本研究的受试者可相对良好地耐受S-1，3级或4级不良事件发生率均低于5%，唯一例外的是3级血红蛋白毒性，累及S-1组9%的患者。白细胞减少或血小板减少等血液学不良事件在S-1组发生率低于吉西他滨组，但S-1组的消化道副作用(如胃炎或腹泻)略多于吉西他滨组。

S-1组和吉西他滨组分别有28%和42%的患者中止治疗，主要原因是毒性或癌症复发。

韦恩州立大学消化肿瘤多学科小组组长Philip A. Philip博士评论指出，S-1将有望成为日本的胰腺癌标准治疗。“我认为，应考虑在非日本人群中开展研究以确定S-1在这些患者中的地位，特别是要评估更小剂量S-1以及该药联合其他抗癌药物对白人患者的疗效与安全性，还应当探寻可用于确定对S-1应答最佳的患者的生物标志物。”

纽约纪念Sloan-Kettering癌症中心的Kenneth H. Yu博士评论称，Uesaka博士的研究令人印象深刻，将会在美国引起更广泛的讨论。

S-1的生产商日本大鹏制药资助了这项研究。Uesaka博士接受了由大鹏和礼来提供的酬金。部分合著者从大鹏和其他制药公司接受了研究资金。Philip博士承认与多家制药公司存在利益冲突，但不包括大鹏制药。

相关评论：一种可能比吉西他滨更好的辅助化疗药物

如今，尽管有1/3的患者可接受潜在治愈性的手术，但胰腺癌在全球范围内仍是一种高度致命的疾病。这些可接受手术的患者中，我们已经将吉西他滨视为标准辅助治疗以改善生存。而这项研究使我们首次掌握了可能比吉西他滨更好的另一种选择。

Neal J. Meropol博士

口服卡培他滨在美国已获准用于治疗多种癌症，通过在血中转化为5氟尿嘧啶(5-FU)而发挥药效。S-1与其相似，但还包含其他成分。S-1含有3种活性成分，其中替加氟可在血中转化为5-FU，后者是胰腺癌和其他类型癌症的常用药；吉美拉西和氧嗪酸是用于增强替加氟的疗效和减少其副作用。

评论专家Neal J. Meropol博士是凯斯西储大学血液与肿瘤系主任。他是作为新闻发布会主持人发表上述评论的。他是Precision Therapeutics的顾问。

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By: SHERRY BOSCHERT, Oncology Practice

SAN FRANCISCO – Japanese patients who underwent surgery for pancreatic cancer were 44% less likely to die within 2 years if they were treated postoperatively with the chemotherapy drug S-1, compared with those given gemcitabine, an interim analysis of an ongoing phase III clinical trial found.

S-1 is not approved in the United States but is used in Japan to treat pancreatic cancer and several other cancers. A separate phase III clinical trial in the United States is underway to study S-1 in the treatment of stomach cancer, several oncology experts said in a press briefing held by the American Society of Clinical Oncology (ASCO).

The current Japanese study randomized 385 patients with pancreatic cancer to postoperative adjuvant therapy with S-1 or gemcitabine. A preplanned interim analysis conducted after the first 205 deaths found that 70% of the 187 patients on S-1 were alive at 2 years, compared with 53% of the 191 patients on gemcitabine, Dr. Katsuhiko Uesaka and his associates reported at a meeting on gastrointestinal cancers.

Patients in the S-1 group also were less likely to relapse. At 2 years, 49% on S-1 were free of disease progression, compared with 29% on gemcitabine, said Dr. Uesaka, medical deputy director of the Shizuoka (Japan) Cancer Center Hospital. The median time to disease progression was 23 months on S-1 and 11 months on gemcitabine.

The study is ongoing; a final analysis is planned after 240 deaths.

S-1 is an oral fluoropyrimidine that combines tegafur, gimeracil, and oteracil. It is approved in Europe for the treatment of gastric cancer at a lower dose than is used in Japan because the drug causes higher rates of diarrhea in white patients. "If the dose and schedule are optimized or adjusted, I expect that S-1 may be applicable for Caucasian patients with pancreatic cancer," he said. "I also expect that some kind of clinical study with S-1 will be done among Caucasian patients with pancreatic cancer."

Patients in the Japanese study tolerated S-1 relatively well, with rates of grade 3 or 4 adverse events below 5% for all except grade 3 hemoglobin toxicity, which affected 9% in the S-1 group. Rates of hematologic adverse events such as leukocytopenia or thrombocytopenia were lower with S-1, compared with gemcitabine, but the S-1 group had slightly higher rates of GI side effects such as stomatitis or diarrhea, he said.

Twenty-eight percent of patients in the S-1 group and 42% in the gemcitabine discontinued treatment, mainly because of toxicity or cancer recurrence, Dr. Uesaka said.

Dr. Philip A. Philip, who discussed Dr. Uesaka’s study at the meeting, said it’s likely that S-1 will become the standard of care for pancreatic cancer treatment in Japan. "In my opinion, non-Japanese studies must be considered to define the role of S-1" in non-Japanese populations, said Dr. Philip, leader of the gastrointestinal cancer multidisciplinary team and professor of medicine and oncology at Wayne State University, Detroit.

Studies should examine the feasibility of using a lower dose of S-1 in non-Japanese populations, he suggested, and explore S-1 treatment for early- and late-stage pancreatic cancer, use of the drug with other cancer drugs or drug combinations, and potential biomarkers that might identify which patients will respond best to S-1.

In a press briefing before the meeting, Dr. Kenneth H. Yu called the results from Dr. Uesaka’s study "very impressive." The findings "will lead to a lot more discussion about whether or not S-1 can be developed for use in the U.S. population," said Dr. Yu of Memorial Sloan-Kettering Cancer Center, New York.

The meeting was cosponsored by ASCO, the American Gastroenterological Association Institute, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Taiho Pharmaceutical Company, which makes S-1, funded the study. Dr. Uesaka has received honoraria from Taiho and Eli Lilly and Co. Some of his associates in the study have received honoraria or research funding from Taiho or other pharmaceutical companies. Dr. Philip disclosed financial relationships with multiple pharmaceutical companies, though not with Taiho.

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A potentially better adjuvant than gemcitabine

To put this into perspective, pancreatic cancer worldwide remains a highly lethal disease, yet about a third of patients who present with pancreatic cancer can undergo surgery with potentially curative intent. Among these patients, we’ve viewed gemcitabine as the standard adjuvant therapy to improve survival over surgery alone. For the first time, we now have another option that appears superior to gemcitabine in this setting, improving the cure rate for patients with pancreatic cancer that is resectable.

S-1 is an oral formulation that contains three different components. One component, tegafur, is turned into 5-fluorouracil (5-FU) in the bloodstream. 5-FU is a commonly used drug in pancreatic cancer and other types of cancers worldwide. The other components of S-1 are added to improve the effectiveness of the tegafur and to reduce its side effects.

Oral capecitabine, which is available in the United States for a variety of cancers, also gets turned into 5-FU in the bloodstream. S-1 is similar, but with these other ingredients. S-1 is licensed in other countries and is in clinical development with the potential for future licensing in the United States. There’s a question of dosing and how the side effects profile might differ in different populations.

Dr. Neal J. Meropol is chief of hematology and oncology at Case Western Reserve University, Cleveland. He gave these comments as moderator of the press briefing. He has been a consultant or advisor to Precision Therapeutics.