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作者：Nick Mulcahy  
出處：WebMD醫學新聞

　　October 21, 2009 — 根據10月22日新英格蘭醫學期刊(New England Journal of Medicine)一篇有255個孩童的新隨機試驗結果，治療罕見的兒童肝母細胞瘤時，對於標準風險病患，單以cisplatin治療並沒有比併用cisplatin和doxorubicin的結果差。
　　
　　義大利Padua大學醫院的Giorgio Perilongo醫師所領導的國際研究團隊指稱，使用cisplatin的小孩的完整切除率和存活率，與接受併用治療的小孩相似。
　　
　　Perilongo醫師向Medscape Oncology表示，我們建議，對所有標準風險病患，單以cisplatin治療即可。
　　
　　完整切除率是該試驗的初級終點，單以cisplatin治療組為95%，併用cisplatin和doxorubicin組為93%。
　　
　　單以cisplatin治療組的三年無意外存活率與整體存活率分別為83%和95%，併用cisplatin和doxorubicin組為85%和93%。這些小孩的追蹤期間中位數為46個月。
　　
　　「International Childhood Liver Tumour Strategy Group 3 (SIOPEL 3)」這項試驗的研究者寫道，相似的無意外存活率與整體存活率顯示，對於標準風險肝母細胞瘤病童可以明確的治療。
　　
　　可預期的是，單一治療比較沒有毒性。急性等級3或4的事件，包括發熱性嗜中性球減少症，在併用cisplatin和doxorubicin組比單以cisplatin治療組多出許多(74.4% vs 20.6%)。
　　
　　不過，Perilongo醫師等人指出，對於局部擴大肝母細胞瘤病童，初步手術以及輔以cisplatin為基礎的多種藥劑化療，可以獲得相當好的結果。他們解釋，這些不同研究的風險分類差異使得研究者無法進行直接比較。
　　
　　Perilongo醫師表示，目前的研究並未包括任何高風險疾病的孩童。這些病患更難治療，也是肝母細胞瘤領域的未來挑戰之一。
　　
　　他表示，肝母細胞瘤研究的下一步是重整我們的風險分類，以能後續減少治療，改善高風險肝母細胞瘤病童的治療，根據新藥劑發展生物驅動治療方法。
　　
　　【建立在過去的研究基礎】
　　SIOPEL 3試驗是該研究團隊過去兩篇研究的後續成果。在SIOPEL 1試驗中，研究者給予cisplatin–doxorubicin且確認兩個治療前的預測因子：肝內腫瘤擴大以及肺轉移。根據這些發現，他們建立了治療前風險分組：標準風險(腫瘤侷限在肝臟且沒有超過 3個肝段)，以及高風險(腫瘤包括整個肝臟與其他)。
　　
　　在SIOPEL 2試驗中，也是現在這個試驗究的先驅研究，研究者首次嘗試cisplatin單一治療，靈感來自另外一篇試驗(J Clin Oncol. 2000;18:2665-2675)，顯示不含antracycline的多藥劑處方和cisplatin–doxorubicin一樣有效且沒有心臟毒性。
　　
　　新研究中，使用「治療前腫瘤擴大系統(pretreatment tumor extension system，PRETEXT)」對腫瘤擴大進行分級。只有標準風險病患(PRETEXT等級1-3者)適合，所有孩童年紀都小於16歲。
　　
　　在1998至2006年間，126個小孩被指定使用cisplatin單一治療(每14天)，129人指定使用cisplatin–doxorubicin (每21天)。兩組的手術前化療療程中位數都是4次。根據腫瘤反應為孩童進行切除手術，之後給予術後化療(兩組的療程中位數都是2次)。
　　
　　研究者表示，選定完整切除率作為初級終點的理由是，這實際上是這些病患長期存活和無意外存活的最重要預測因素。
　　
　　【病患數不夠多】
　　作者們指出，在這不劣性試驗設計中，他們無法在統計上證明有關這兩種處方的結論是可比擬的。他們的理由是，病患數量有限；不過，無意外存活率與整體存活率相似可以支持單用cisplatin治療並不差。
　　
　　就負面結果來說，單一治療組有19個病患(15%)、併用cisplatin和doxorubicin組有15個病患(12%)出現疾病惡化或復發。單一治療組有7個小孩、併用cisplatin和doxorubicin組有8個小孩死亡。
　　
　　試驗的所有病患約有三分之一出現聽力損失(168人中有53人)；不過，兩組之間沒有差異。
　　
　　至於心臟毒性，研究者表示，有此影響的病患少，需要更長期的追蹤來適當評估任何的不良影響。
　　
　　作者們寫道，重要的是，在試驗中，研究協定有修改，α-胎兒蛋白值低於100 ng/mL的小孩被排除，因為有明確證據認為這些病患的結果不佳。
　　
　　研究者宣告沒有相關財務關係。  

In Hepatoblastoma, Cisplatin Monotherapy Is Just as Good as Combo

By Nick Mulcahy
Medscape Medical News

October 21, 2009 — In the treatment of the rare childhood disease of hepatoblastoma, a simple monotherapy with cisplatin is not inferior to a combination of cisplatin and doxorubicin in patients with "standard-risk" disease, according to the results of a new randomized trial of 255 children published in the October 22 issue of the New England Journal of Medicine

The children receiving cisplatin had rates of complete resection and survival similar to those in children receiving the combination adjuvant therapy, according to the international group of authors, led by Giorgio Perilongo, MD, from the University Hospital of Padua in Italy.

"We recommend the use of cisplatin alone for all standard-risk hepatoblastoma," Dr. Perilongo told Medscape Oncology.

The rate of complete resection, which was the trial's primary end point, was 95% in the cisplatin-monotherapy group and 93% in the cisplatin–doxorubicin group.

Three-year event-free survival and overall survival were, respectively, 83% and 95% in the monotherapy group and 85% and 93% in the cisplatin–doxorubicin group. The children were followed for a median of 46 months.

The similar event-free and overall survival rates "bode well for the definitive cure of children with standard-risk hepatoblastoma," write the investigators of the trial, known as International Childhood Liver Tumour Strategy Group?3 (SIOPEL?3).

Predictably, the monotherapy was also less toxic. Acute grade?3 or 4 events, including febrile neutropenia, were much more frequent in the cisplatin–doxorubicin group than in the monotherapy group (74.4% vs 20.6%).

However, Dr. Perilongo and his colleagues noted that strategies consisting of primary surgery and adjuvant multiagent cisplatin-based chemotherapy have resulted in "excellent outcomes" in children with limited extension hepatoblastoma. Differences in risk stratification between these various studies did not allow the investigators from making direct comparisons, they explain.

The current study did not include any children with high-risk disease. These patients are more difficult to treat and are part of the future challenges in hepatoblastoma, said Dr. Perilongo.

"The next steps in hepatoblastoma research are to refine our risk stratification in order to further reduce therapy, improve the cure of children with high-risk hepatoblastoma, and develop a biological drive therapeutic approach based on new agents," he said.

Building on Past Studies

SIOPEL?3 is an outgrowth of the findings of the group's 2 earlier trials. In SIOPEL?1, the investigators administered cisplatin–doxorubicin and identified 2 pretreatment prognostic factors: intrahepatic tumor extension and lung metastases. Based on these findings, they established pretreatment risk groups: standard risk (tumor confined to the liver and not more than 3 hepatic sectors) and high risk (tumors involving the entire liver and beyond).

In SIOPEL?2, which was a pilot study for the current trial, the researchers tried cisplatin monotherapy for the first time, using insight from another trial (J Clin Oncol. 2000;18:2665-2675) that showed a multiagent antracycline-free regimen was just as effective as cisplatin–doxorubicin but with no cardiotoxicity.

In the new study, tumor extension was graded using the pretreatment tumor extension system (PRETEXT). Only standard-risk patients (those with PRETEXT grades?I–III) were eligible, and all children had to be younger than 16 years.

Between 1998 and 2006, 126 children were assigned to cisplatin monotherapy (every 14 days) and 129 to cisplatin–doxorubicin (every 21 days). The median number of cycles of preoperative chemotherapy was 4 in both groups. The children were resected on the basis of tumor response and then administered postoperative chemotherapy (both groups had a median of 2 cycles).

The rate of complete resection was chosen as the primary end point for a number of reasons, including the fact that it is the "single most important prognostic factor for long-term survival and event free-survival" in these patients, say the authors.

Not Quite Enough Patients

The authors noted that, in this noninferiority design, they could not statistically prove their conclusion that the 2 regimens were comparable. The reason was the limited number of patients; still, the similar rates of event-free survival and overall survival "provide support" for the noninferiority of cisplatin monotherapy, they argue.

In terms of negative outcomes, 19 patients in the monotherapy group (15%) and 15 in the cisplatin–doxorubicin group (12%) had disease progression or relapse. Seven children in the monotherapy group and 8 in the cisplatin–doxorubicin group died.

Some hearing loss was documented in about a third of all patients tested (53 of 168); however, there was no difference between the 2 groups.

With regard to cardiotoxicity, the investigators said that the small number of affected patients required "longer follow-up" to accurately assess any impairments.

Importantly, during the trial, the protocol was amended and children with alpha-fetoprotein levels of less than 100?ng/mL were excluded because of "mounting evidence of a poor outcome in these patients," write the authors.

The researchers have disclosed no relevant financial relationships.

New Engl J Med. 2009;361:1662-1670.