第一期小細胞肺癌只有進行手術是合理的

作者：Fran Lowry  
出處：WebMD醫學新聞

　　February 25, 2010 — 國家癌症研究中心的「流行病監測及最終結果(SEER)」資料庫分析結果顯示，第一期小細胞肺癌(SCLC)只有進行手術但無放射線治療似乎也可以提供合理的存活結果。
　　
　　這些研究發現使研究者結論認為，肺葉切除術本身是一個可行的選項。
　　
　　耶魯大學的James B. Yu醫師領導的此一分析，登載於2月份的胸肺腫瘤期刊(Journal of Thoracic Oncology)。
　　
　　傳統上，第一期SCLC會進行放射線治療與化療，但是，現在的研究顯示，接受手術和化療的病患也有合理的存活結果，不過，作者們在文章中指出，目前的研究結果之間各異。
　　
　　Yu醫師等人是在看到一個原本被認為是非小細胞肺癌、最後證明是第一期SCLC的病患之後，著手研究此一議題。
　　
　　他向Medscape Oncology表示，我們不知道最近是否有任何研究探討這個病患是否需要後續的放射線治療，特別是目前有更好的化療與改善的分期技術，因此我們決定對SEER資料庫進行分析。
　　
　　他們的研究對象包括了於1988-2004年間接受手術切除的247名第一期SCLC病患，年紀中位數為70歲(範圍：27– 94歲)。這些人之中，205名(83%)接受肺葉切除術但無放射線治療，38名(15%)接受放射線治療；有4名病患不知道有無使用放射線治療。
　　
　　研究者發現，接受肺葉切除術但無放射線治療者的5年整體存活率為50.3%(95%信心區間[CI]為43.1%- 57.1%)；至於接受肺葉切除術與放射線治療者，5年整體存活率為57.1% (95% CI，37.4%- 72.7%)。
　　
　　Yu醫師指出，這是令人興奮的研究發現，也開啟了臨床試驗的一扇門，不過，他承認，建構這類試驗有其困難。
　　
　　有另外兩名肺癌專家對於臨床試驗的想法有不同意見，其看法是不具可行性，這類病患手術的價值是存疑的。
　　
　　【強調研究限制】
　　Yu醫師強調，這個研究有幾個限制。
　　
　　這是一個對SEER資料庫的分析，有固有的取樣偏差，有許多不清楚的資訊，例如，我們不知道為何某些病患接受放射線治療、使用的又是哪種放射線，此外，我們假定所有病患都接受化療，但是，資料庫中沒有他們接受的化療的資訊，我們能說的只有，第一期SCLC病患在只有進行手術之後，似乎有合理的存活，而這是目前為止唯一可得到的結論。
　　
　　他表示，多數小細胞肺癌病患出現廣泛的疾病，只有很少數是真正的第一期疾病，我們探討的是整個SEER資料庫，但是只有分析1988-2004年間的1,560名第一期小細胞肺癌病患，這16年的全國資料等於每年只有分析大約100個病患。
　　
　　Yu醫師指出，或許很難進行隨機試驗，但是仍有可能，我們真的需要這類病患只有進行手術時結果的答案。
　　
　　【該是時候做出決定了】
　　多倫多大學的Frances Shepherd醫師在編輯評論中表示同意，呼籲進行國際性的前瞻隨機控制試驗，探討化療與放射線規範的彈性，且儘可能拉長研究期間，以回答這個延宕許久但又相當重要的問題。
　　
　　不過，Shepherd醫師質疑，在以鉑為基礎的化療領域中，且具有同時安全地進行高劑量胸腔放射線治療的能力、有可接受的急性與延遲毒性程度下，手術是否是最佳治療方式、甚至是否必須要手術。
　　
　　然而，重點在有這類試驗，即便第一期SCLC的病患族群這麼少。
　　
　　Shepherd醫師寫道，這類病患很少(可能不到10%)，所以可能只能透過國際間的合作，進行前瞻隨機試驗來證明或反駁手術適合這類病患。
　　
　　她指出，也該是停止SCLC手術之單一機構研究報告與資料庫分析的時候了。
　　
　　她結論表示，胸腔腫瘤科醫師必須決定要釣魚還是切斷魚餌，如果他們決定釣魚，國際學界必須合作進行前瞻試驗，或許可能只有一個機會來進行這個指標性的試驗，讓我們放手去做吧！
　　
　　【這類試驗不可行】
　　華盛頓西雅圖瑞典癌症研究中心的Howard West醫師受Medscape Oncology之邀發表獨立評論時表示，進行這類研究將相當有挑戰性。
　　
　　SCLC目前佔美國肺癌的13%以下，且比率逐漸降低，結節陰性案例可能可以視為適合隨機進行手術，這代表不到10%的SCLC病患，所以，需要國際性的協調進行試驗，我認為，許多醫師和病患可能反對隨機分組，整體而言，我擔心這類試驗是不可行的。
　　
　　West醫師指出，詮釋SCLC的手術價值時，重要且不可或缺的問題是，它是這麼少(約10%)的結節陰性病患的一個選項，他認為，這些病患可能還有相當不同的自然史的疾病。
　　
　　我們無法、也不應假設他們和其他90%迅速擴散的SCLC案例有同樣的自然史，呈現相當局部之SCLC且沒有結節擴散的病患，就是我們可以推定相當非典型生物學的SCLC類型，他們的治療效果可能比那些為數較多的結節陽性或擴散病患要好得多。
　　
　　化療是SCLC治療的基石，West醫師表示，這類治療有其危險性，就治療而言，價值上也是會受質疑。
　　
　　他指出，放射線技術正穩定地逐步改善，當有其他效果相當而毒性較小的治療時，他質疑病患是否會接受手術的發病率。
　　
　　Yu醫師、Shepherd醫師與 West醫師皆宣告沒有相關財務關係。


Surgery Alone May Be Reasonable for Stage I Small-Cell Lung Cancer

By Fran Lowry
Medscape Medical News

February 25, 2010 — An analysis of outcomes from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database indicates that surgery without radiotherapy for stage?I small-cell lung cancer (SCLC) "appears to offer reasonable survival outcomes."

The findings led researchers to conclude that lobectomy by itself is a viable option.

The analysis, headed by James B. Yu, MD, from Yale University in New Haven, Connecticut, appears in the February issue of the Journal of Thoracic Oncology.

Traditionally, stage?I SCLC has been treated with radiation and chemotherapy, but modern studies have shown reasonable survival in patients who undergo surgery and chemotherapy. However, as the authors point out in their article, results from existing trials have been conflicting.

Dr. Yu and his colleagues were prompted to study the issue after they were presented with a patient who was originally thought to have nonsmall-cell lung cancer, which turned out to be stage?I SCLC.

"We didn't know whether there were any studies that had recently looked at whether this patient needed further radiation or not, especially in light of better chemotherapy and improved staging techniques, and that is when we decided to take a look in the SEER database," he told Medscape Oncology.

The investigators identified 247 patients with stage?I SCLC who underwent surgical resection between 1988 and 2004. Their median age was 70 years (range, 27?- 94 years). Of this codort, 205 patients (83%) had lobectomy without radiation therapy and 38 (15%) received radiation therapy; the use of radiation was unknown in 4 patients.

The researchers found that the 5-year overall survival in patients who underwent lobectomy without radiation was 50.3% (95% confidence interval [CI], 43.1%?- 57.1%); for patients who had lobectomy with radiation, the 5-year overall survival was 57.1% (95% CI, 37.4%?- 72.7%).

Dr. Yu added that the findings are provocative and open the door to a clinical trial, although he conceded that mounting such a trial would be difficult.

Two outside lung cancer experts had different opinions on the idea of a clinical trial, with one saying it was not feasible and that surgery in these patients was of "questionable value."

Limitations Stressed

Dr. Yu stressed that his study has several limitations.

"This is an analysis of the SEER database. There is inherent selection bias and there is a lot of information that we just do not know. For instance, we don't know why some patients got radiation, or what kind of radiation they did get. In addition, we have assumed that all patients got chemotherapy, but there is no information in the database about which chemotherapy they received. All we can say is that people who have a stage?I SCLC seem to have reasonable survival after surgery alone. But that is as far as we can go in terms of a conclusion."

It would be difficult to do a randomized trial.

"Most small-cell lung cancer patients present with extensive disease. Only a very small minority have true stage?I disease. We looked at the entire SEER database and only analyzed 1560 patients with stage?I small-cell lung cancer between 1988 and 2004. That is 16 years of national data, yielding only about 100 patients a year," he said.

"It would be difficult to do a randomized trial but it is possible, and it is what we definitely need to answer the question of the utility of surgery alone for such patients," Dr. Yu added.

It's Time to Fish or Cut Bait

In an accompanying editorial, Frances Shepherd, MD, from the University of Toronto in Ontario, agreed, calling for an international prospective randomized controlled trial with flexible chemotherapy and radiation protocols that would be allowed to run as long as necessary "to answer this lingering but important question."

However, Dr. Shepherd questions whether surgery is the best treatment or even necessary "in this era of platinum-based chemotherapy and the ability to administer concurrent thoracic radiotherapy in high doses safely and with acceptable levels of acute and late toxicity."

Nevertheless, it would be important to have such a trial, even though the proportion of patients with stage?I SCLC is so low.

"Very few patients fall into this subgroup (likely less than 10%), and so it would only be possible to mount a prospective randomized trial to prove or disprove that surgery is appropriate in this setting through international multidisciplinary collaboration," Dr. Shepherd writes.

There is probably only 1 more chance to mount this potentially 'landmark trial.'

It is also time to stop reporting on single-institution studies and database analyses of surgery for SCLC, she adds.

"Thoracic oncologists must decide to 'fish or cut bait.' If they decide to 'fish,' the international community must come together for a prospective trial," she concludes. "There is probably only 1 more chance to mount this potentially 'landmark trial.' Let's go fishing!"

Such a Trial Not Feasible

It would be exceptionally challenging to conduct such a trial, said Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, who was approached by Medscape Oncology for independent comment.

I think many physicians and patients would also be resistant to randomization.

"SCLC now accounts for less than 13% of lung cancers in the United States, and that proportion continues to decline. Node-negative cases that would be considered appropriate for randomization to surgery represent less than 10% of that SCLC population, so an internationally coordinated trial would be required. I think many physicians and patients would also be resistant to randomization. Overall, I fear that such a trial simply isn't feasible."

Dr. West pointed out that a significant and integral problem in interpreting the value of surgery in SCLC is that it is an option for such a small proportion of patients — about 10% — who have node-negative disease. These patients might well have disease with a very different natural history, he suggested.

"We can not and should not presume they have the same natural history as the other 90% of SCLC cases that present with more rapidly disseminating disease. The patients who present with a very localized SCLC and no nodal spread are precisely the patients who we might presume have a very atypical biology for SCLC that may have them do far better with any treatment than the more representative cases of SCLC that present with nodal involvement or more widespread disease."

Chemotherapy is a cornerstone of SCLC therapy. Dr. West cautioned about the danger of compromising the ability to deliver this treatment "in the name of a treatment that still has questionable value."

He added that radiation techniques are constantly and steadily improving, and questioned whether patients should accept the morbidity of surgery when treatments that have comparable efficacy and less toxicity are available.

Dr. Yu, Dr. Shepherd, and Dr. West have reported no relevant financial relationships.

J Thorac Oncol. 2010;5:1497-149, 215-219.