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作者：Nick Mulcahy  
出處：WebMD醫學新聞

　　【24drs.com】October 29, 2009 – 10月24日的Lancet期刊發表了歐美據以核准pemetrexed(商品名Alimta，Eli Lilly藥廠)用於末期非鱗狀非小細胞肺癌(NSCLC)病患之維持治療的一篇臨床試驗。
　　
　　Pemetrexed限用於使用白金製劑治療後沒有惡化的病患，不適用於使用pemetrexed作為初始治療之一部份的病患。
　　
　　在這項新試驗中的統計顯示，pemetrexed這種靜脈注射化療劑可明顯改善整體存活。
　　
　　研究資料發表於6月的美國臨床腫瘤協會(ASCO)會議中。當時，發表人、賓州癌症癌中心的Chandra P. Belani醫師將pemetrexed維持治療形容為肺癌病患的「新治療典範」；Belani醫師也是新發表文獻的資深作者。
　　
　　不過，ASCO有兩位肺癌專家在Medscape Oncology訪問時表示不同意Belani醫師的看法，認為不清楚何時該開始使用 pemetrexed — 應該在初始治療之後(作為維持治療)或者當發生惡化時(作為二線治療)。
　　
　　Nasser H. Hanna醫師當時的評論是，我不認為所有病患都需要在第一線治療之後立即進行維持治療。
　　
　　來自印第安那大學的Hanna醫師也指出，該試驗的設計並未針對維持治療是否優於在疾病惡化時才使用pemetrexed進行檢測。
　　
　　現在，針對新發表之研究的編輯評論也呼應這些有關治療時機的看法。
　　
　　北卡羅來納大學的Thomas E. Stinchcombe醫師與西雅圖瑞典癌症研究中心的Howard J. West醫師等編輯寫道，新資料並未明確顯示後續治療的時機是重要的，不過，他們也重申，pemetrexed可顯著改善存活。
　　
　　【時機是病患選項】
　　編輯們認為，使用pemetrexed作為維持治療是病患的選擇。
　　
　　他們寫道，對於第一線化療有反應或病情穩定的病患、可耐受以白金製劑為基礎的治療而無限制毒性且維持良好表現狀態者，以及想要持續治療者，維持治療是一個有吸引力的考量。
　　
　　不過，有些病患可能是偏好將pemetrexed作為第二線治療。Stinchcombe醫師與West醫師寫道，如果病患對第一線治療產生毒性、或者需要暫停治療之間隔，則需密切觀察且在疾病進展時即時開始第二線治療，將會是適合的替代方案。
　　
　　不過，West醫師在他的Medscape肺癌部落格上，寫出對於有多少腫瘤科醫師有興趣建議維持治療感到懷疑，不論是pemetrexed或erlotinib(OSI Pharmaceuticals藥廠)。最近顯示這類病患使用erlotinib對於整體存活有統計上的顯著改善。
　　
　　他在他的Blowing Smoke部落格寫道，從我和社區開業醫師到胸腔腫瘤專家等、各界的腫瘤科醫師的對話看來，這些正面試驗結果並未造成太大的改變。
　　
　　如果不建議維持治療，醫師們對於非惡化的病患比較會使用哪種治療呢？West醫師寫道，許多腫瘤科醫師似乎比較傾向從第一線治療延伸一種或以上的製劑，直到病況惡化(再更改處方)，而比較不會在四線治療之後轉換一個新治療。
　　
　　【為何維持治療不是一個自動選項】
　　在這新的多中心跨國研究中，NSCLC病患接受標準化療；那些沒有疾病惡化者以二比一的比率隨機分派接受pemetrexed加最佳支持照護，或者安慰劑加最佳支持照護。
　　
　　該試驗的481名非鱗狀NSCLC病患中，pemetrexed的整體存活顯著優於安慰劑(15.5 vs 10.3個月；P?= .002)。
　　
　　編輯們也強調另一個結果—疾病控制。他們指出，非鱗狀NSCLC病患的疾病控制率，pemetrexed組為58%，安慰劑組為33%。
　　
　　他們指出，這是重要的，因為顯示出這些肺癌病患約有三分之一在初始化療之後、沒有額外治療下，有一段疾病穩定期，因此，維持治療將會變成過度治療。
　　
　　編輯寫道，顯然有一類病患的病程相對緩慢，若是在第一線治療之後立即進行後續治療，將會造成過度治療；不過，我們未能明確可信地區分這些病患。
　　
　　編輯們建議，醫師們在決定有關維持治療的建議時，應該也要評估pemetrexed的副作用。他們指出，嚴重毒性的比率低，維持使用pemetrexed的病患只有5%因為藥物相關毒性而停藥，只有5%需要劑量降低。不過，依舊要加以考量。他們寫道，輕微毒性對於病患的生活品質也會有所影響。
　　
　　ASCO會議中，印第安那大學的Hanna醫師提出相同看法，化療的第一和第二級非血液毒性，如腹瀉、紅疹和疲勞，都必須小心注意，以免這些影響生活品質。
　　
　　Belani醫師是贊助本試驗之Eli Lilly藥廠的顧問。

Advice on Timing of Pemetrexed in Advanced Lung Cancer

By Nick Mulcahy
Medscape Medical News

October 29, 2009 – The clinical trial that served as the basis for the approval of pemetrexed (Alimta, Eli Lilly) in the United States and Europe as a maintenance therapy for patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) appears in the October 24 issue of the Lancet.

Pemetrexed is limited for use in patients who have not progressed after platinum treatment. It is not indicated for patients who receive pemetrexed as part of an initial therapy.

In the new trial, pemetrexed, an intravenous chemotherapy, showed a statistically significant improvement in overall survival.

The study data were presented at the American Society of Clinical Oncology (ASCO) meeting in June. At the time, pemetrexed maintenance therapy was described as a "new treatment paradigm" for lung cancer patients by presenter Chandra P. Belani, MD, from the Penn State Cancer Institute in Hershey, Pennsylvania. Dr. Belani is also the senior author of the newly published study.

However, at ASCO, 2 lung cancer experts approached by Medscape Oncology disagreed with Dr. Belani and said that it was not clear when to start pemetrexed — immediately after initial treatment (maintenance therapy) or when progression occurred (second-line therapy).

"I don't think that all patients need immediate maintenance therapy following first-line treatment," Nasser H. Hanna, MD, commented at the time.

Dr. Hanna, who is from Indiana University in Indianapolis, also pointed out that the trial was not designed to test whether maintenance therapy was superior to using pemetrexed at time of disease progression.

Now, an editorial accompanying the newly published study echoes these concerns about treatment timing.

The new data have not "conclusively shown that the timing of subsequent therapy is crucial," write editorialists Thomas E. Stinchcombe, MD, from the University of North Carolina at Chapel Hill, and Howard J. West, MD, from the Swedish Cancer Institute in Seattle, Washington. However, they also reiterate the point that pemetrexed "can significantly improve survival."

Timing Is a Patient Choice

The editorialists suggest that using pemetrexed as a maintenance therapy is very much a patient choice.

"For patients who have a response or stable disease with first-line chemotherapy, who tolerated platinum-based therapy without limiting toxicity while maintaining a good performance status, and who desire to continue therapy, maintenance therapy is an appealing consideration," they write.

However, using pemetrexed as a second-line therapy may be preferred by other patients. "If patients have had substantial toxicity with first-line therapy or desire a treatment-free interval, close monitoring and starting timely second-line therapy at disease progression remains an appropriate alternative," write Drs. Stinchcombe and West.

However, Dr. West, writing in his Medscape blog on lung cancer, expressed doubt about just how many oncologists are interested in recommending maintenance therapy, with either pemetrexed or erlotinib (OSI Pharmaceuticals). A statistically significant improvement in overall survival in this setting has recently been shown with erlotinib.

There isn't a sea change happening in the wake of these positive trials.

"From my conversations with various medical oncologists, ranging from broad community-based practice to thoracic oncology specialists, there isn't a sea change happening in the wake of these positive trials," he wrote in his Blowing Smoke blog.

If not maintenance therapy, what are clinicians more likely to use in patients with nonprogressing disease? "Many oncologists seem far more inclined to extend 1 or more agents from first line until progression than to switch to a new treatment after 4 lines of therapy," Dr. West writes.

Why Maintenance Therapy Is Not an Automatic Choice

In the new multicenter international study, NSCLC patients received standard chemotherapy; those who did not have disease progression were then randomly assigned (2:1 ratio) to receive pemetrexed plus best supportive care or placebo plus the same care.

Among the trial's 481 patients with nonsquamous NSCLC, pemetrexed resulted in statistically significantly better overall survival than placebo (15.5 vs 10.3 months; P = .002).

The editorialists also highlighted another outcome — that of disease control. They point out that the disease control rate in the patients with nonsquamous NSCLC was 58% in the pemetrexed group and 33% in the placebo group.

This is important because it shows that about one third of these lung cancer patients have a period of disease stability after initial chemotherapy — without any additional therapy — and thus would be overtreated by maintenance therapy, they note.

There is clearly a subset of patients with relatively indolent disease who would effectively be overtreated.

"There is clearly a subset of patients with relatively indolent disease who would effectively be overtreated by an immediate transition to further treatment after first-line therapy; however, we cannot reliably identify these patients," write the editorialists.

Clinicians should also evaluate the adverse effects of pemetrexed in making their recommendations about maintenance therapy, the editorialists suggest. They note that the rates of severe toxicity were low, with only 5% of patients on maintenance pemetrexed discontinuing treatment because of drug-related toxicity and only 5% requiring a dose reduction. However, concerns remain. "Mild toxicity can adversely affect a patient's quality of life," they write.

At ASCO, Dr. Hanna from Indiana University noted the same thing, citing the chemotherapy's grade 1 and 2 nonhematologic toxicities, such as diarrhea, rash, and fatigue. "We must be careful not to trivialize these," he said, noting that they affect quality of life.

Dr. Belani is a consultant to Eli Lilly, which sponsored the trial.

Lancet. 2009;374:1398-1400, 1432-1430.