本帖最後由 lsc0019 於 2009-4-7 22:54 編輯
作者：Roxanne Nelson
出處：WebMD醫學新聞
March 25, 2009 — 根據線上登載於3月18日Lancet期刊的一篇報告，輔以imatinib mesylate(Gleevec，Novartis藥廠)可以改善胃腸道基質瘤(gastrointestinal stromal tumors，GIST)病患完整切除後的無復發存活。
Imatinib的此一用途 — 預防GIST的術後復發— 最近被美國食品藥物管理局(FDA)核准作為新增適應症。此產品已經被核准作為轉移性GIST的第一線治療。
這些結果來自一個多中心的第三期試驗，顯示Imatinib組估計一年無復發存活率為98%，而安慰劑組則是83%，整體風險比為0.35 (P< .0001)。這些發現支持第二期單組開放標籤imatinib輔助治療試驗，發表於美國臨床腫瘤協會2008年胃腸道癌症研討會中，當時由Medscape Oncology報導。
不過，兩個研究組之間的整體存活相似。研究者對此並不意外，考量追蹤期相對較短以及交叉型研究設計，准許安慰劑組的病患於發生腫瘤復發時轉為接受imatinib。
主要研究者、紐約市Sloan-Kettering癌症紀念中心一般腫瘤外科主任暨外科副主任Ronald DeMatteo醫師表示，追蹤期更久的時候出現不一樣的存活是有可能的，交叉效果會有很大的影響，也因此迄今少有病患死亡。
DeMatteo醫師向Medscape Oncology表示，目的是長期追蹤病患，看輔助治療是否可以有整體存活利益；這些病患將被追蹤至少10年。
研究設計僅將病患根據腫瘤大小分組，即使回溯研究報告指出，有絲分裂速率以及腫瘤位置等因素也對GIST預後很重要。不過，研究者指出，這些因素並未經前溯研究確認。
DeMatteo醫師表示，試驗於探究腫瘤至少3公分的所有病患有其強度；這些結果顯示在無復發存活上確有差異。
雖然研究在次組分析上不具強度，但他表示，我們是就腫瘤大小進行討論；在所有腫瘤大小分類上，有統計上的顯著差異。
研究者還未提出確認哪些病患最適合輔以治療imatinib的建議。他解釋，我們需分析其他資料，包括有絲分裂速率、位置、以及突變狀態，之後才能提出哪些病患無須治療的具體建議。
DeMatteo醫師也指出，陸軍病理研究中心(AFIP)的Markku Miettinen博士與Jerzy Lasota博士，使用回溯研究資料建立了一個表格顯示GIST復發風險。根據該表格，有些病患大多沒有復發風險，因而無須治療。
【腫瘤大小不是最適合的準則】
在編輯評論中，德國海德堡大學胸腔外科暨腫瘤外科教授Peter Hohenberger醫師指出，imatinib在實體腫瘤安慰劑控制輔助治療研究上，於無復發存活獲得空前的減少。
不過，他強調，研究顯示，腫瘤小於10公分的病患，其無復發存活只有些微改善，而腫瘤更大的病患治療利益最大。
Hohenberger醫師也指出，單只有腫瘤大小並非篩選可以輔助治療病患的最佳準則。他寫道，腫瘤大小超過3公分的GIST病患是高度多樣化的族群，其復發與死亡風險從接近0到100%都有，應該是有實質復發風險的病患才需要接受imatinib輔助治療。
他向Medscape Oncology表示，根據AFIP準則，治療應限於實際高風險者，不應給予因為一些分子學原因而已知無效的病患 。
【改善無復發存活】
DeMatteo醫師等人的研究對象是713名原發 GIST、大小至少3公分、接受完整可見腫瘤切除的病患。這些病患中，359人被隨機分派接受每天400 mg的治療一年，354人被隨機分派接受安慰劑；安慰劑組病患發生腫瘤復發者可轉為imatinib組。
在平均追蹤19.7個月中，imatinib組有8% (n= 30)的病患發生腫瘤復發或者死亡，安慰劑組則是20% (n= 70)。Imatinib顯著改善了無復發存活，在回溯分析中，三組不同腫瘤大小的病患都有此一利益。
研究作者發現，使用imatinib病患的復發率，似乎在手術後約18個月或者研究治療完成後6個月增加。他們也強調，輔助治療對於高風險病患特別有意義，包括那些腫瘤10公分以上或者有絲分裂速率高的病患，在沒有輔助治療的兩年時，有超過50%的機會復發。
國家癌症研究中心、國家健康研究中心、提供imatinib與安慰劑的Novartis藥廠共同資助本研究。DeMatteo醫師以及多位共同作者報告接受Novartis的獎助金以及擔任Novartis諮詢委員。 Hohenberger 醫師報告接受來自Novartis的研究資金以及獎助金。
Lancet. 於印行前，線上發表於2009年3月18日。
Adjuvant Imatinib Reduces Risk for Recurrence of GIST
By Roxanne Nelson
Medscape Medical News
March 25, 2009 — Adjuvant imatinib mesylate (Gleevec, Novartis) appears to improve recurrence-free survival in patients with gastrointestinal stromal tumors (GIST) following complete resection, according to a report published online March 18 in the Lancet.
This use for imatinib — for the prevention of postoperative recurrence of GIST — was recently approved by the US Food and Drug Administration as an additional indication. The product was already approved for use in the first-line treatment of metastatic GIST.
The results come from a multicenter phase?3 trial, and show that the estimated 1-year recurrence-free survival for the imatinib group was 98%, compared with 83% for the placebo group, with an overall hazard ratio of 0.35 (P?< .0001). These findings support those from a phase?2 single-arm open-label trial of imatinib in the adjuvant setting that was presented at the American Society for Clinical Oncology 2008 Gastrointestinal Cancers Symposium, and reported by Medscape Oncology at that time.
However, overall survival was similar between the 2 study groups. The researchers were not surprised by this, considering the relatively short follow-up period and the crossover design of the study, which permitted patients in the placebo group to receive imatinib upon tumor recurrence.
"It is certainly possible that longer follow-up may show a survival difference," said lead author Ronald DeMatteo, MD, vice chair of the Department of Surgery and head of the Division of General Surgical Oncology at Memorial Sloan-Kettering Cancer Center, in New York City. "The crossover effect has a huge impact, and that is why so few patients have died thus far."
The intention is to follow the patients long term, to see if there is an overall survival benefit from adjuvant use. "These patients will be followed for at least 10 years from trial entry," Dr. DeMatteo told Medscape Oncology.
The study was designed to stratify patients only on the basis of tumor size, even though retrospective studies have reported that factors such as mitotic rate and tumor site might also have prognostic importance in GIST. However, none of these features have been validated prospectively, the researchers note.
"The trial was powered to look at the entire population of patients with at least 3?cm tumors," said Dr. DeMatteo. "The results showed a definite difference in recurrence-free survival."
The results showed a definite difference in recurrence-free survival.
Although the study was not powered for subset analysis, "we showed it anyway in terms of tumor size," he said. "There were statistically significant effects in all size categories."
The researchers have not yet formulated a recommendation identifying which patients are the best candidates for adjuvant therapy with imatinib. "We are analyzing other data, including mitotic rate, location, and mutation status, before we make definite recommendations about whether any group should not be treated," he explained.
Dr. DeMatteo also pointed out that Markku Miettinen, MD, PhD, and Jerzy Lasota, MD, PhD, from the Armed Forces Institute of Pathology (AFIP), created a table showing the risk for recurrence of GIST using data from retrospective studies. According to the table, some patients have almost no risk for recurrence, and therefore should not be treated.
Tumor Size Not Most Appropriate Criteria
In an accompanying editorial, Peter Hohenberger, MD, professor in the Division of Surgical Oncology and Thoracic Surgery at the University of Heidelberg, in Germany, points out that imatinib yielded "an unprecedented reduction in recurrence-free survival" for an adjuvant placebo-controlled study involving a solid tumor.
However, he emphasizes that the study showed only a marginal improvement in recurrence-free survival among patients with tumors that were less than 10?cm, and that the greatest benefit was seen in those with larger tumors.
To receive adjuvant imatinib, patients should be at substantial risk of relapse.
Dr. Hohenberger also notes that tumor size alone is not the most appropriate criteria for selecting patients for adjuvant therapy. "Patients with GIST of more than 3?cm are a highly heterogeneous population, within which the risk of relapse and death varies from close to 0 to almost 100%," he writes. "To receive adjuvant imatinib, patients should be at substantial risk of relapse."
"Treatment should be limited to real high risk, according to the AFIP criteria, and should not be given to patients in whom we know that it can't work because of molecular reasons," he told Medscape Oncology.
Improved Recurrence-Free Survival
The study by Dr. DeMatteo and colleagues was conducted in 713 patients who had a primary GIST at least 3?cm in size and who had undergone complete gross tumor resection. Of this group, 359 were randomized to receive 400?mg of imatinib daily for 1 year, and 354 were randomized to receive placebo. Patients in the placebo group who experienced a tumor recurrence were eligible to switch to the imatinib group.
At a median follow-up of 19.7 months, 8% (n?= 30) of patients in the imatinib group experienced a tumor recurrence or died, compared with 20% (n?= 70) of patients in the placebo group. Imatinib significantly improved recurrence-free survival, and this benefit was observed in each of the 3 size categories on retrospective analysis.
The researchers found that the recurrence rate among patients using imatinib seemed to increase after about 18 months from surgery or 6 months after the completion of study therapy. They also emphasize that adjuvant therapy is especially relevant for high-risk patients, including those with tumors 10?cm or larger or with a high mitotic rate, who can have a greater than 50% chance of recurrence at 2 years without adjuvant therapy.
The study was funded by grants from the National Cancer Institute, the National Institutes of Health, and Novartis, which provided imatinib and the placebo. Dr. DeMatteo and several coauthors reported receiving honoraria from Novartis and have served on Novartis advisory boards. Dr. Hohenberger reported receiving research grants and honoraria from Novartis.
Lancet. Published online before print March 18, 2009. |
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