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作者：Zosia Chustecka  
出處：WebMD醫學新聞

　　February 11, 2010 — 根據一項於2月10日線上發表在Lancet腫瘤學期刊的主編評論，全新的生物製劑denosumab（Amgen藥廠）可以提供罕見的骨骼巨細胞腫瘤劃時代的治療。這篇主編評論之後一項小型開放標記研究，報告這個藥物對35位病患的其中30位產生腫瘤反應（86%）。
　　
　　該項研究的主編為德國柯倫Witten-Herdecke大學外傷與骨外科部Maurice Balke醫師、Jendrik Hardes醫師，他們寫到，就我們所知，這是第一個清楚顯示這個罕見腫瘤型態有潛力治療選擇的報告。有少數報告指出，雙磷酸鹽類藥物會有好處，但沒有成功的前瞻性研究。
　　
　　主編們指出，目前骨骼巨細胞腫瘤的治療為外科手術。如果仔細地清除腫瘤，90%以上病例是可以痊癒的。
　　
　　他們進一步指出，仍然有部分非典型巨細胞腫瘤的病例，會有多重局部再發、多中心再發、肺部轉移或是無法以外科手術移除且不會顯著發病的病灶。
　　
　　對於典型良性病灶，造成主要功能缺陷的外科手術很難適用，但是直到現在，並沒有具潛力的替代治療。幸運的是，這將改變了。這個傑出的研究可能改變目前對於複雜性骨骼巨細胞腫瘤的治療模式。
　　
　　Denosumab目前還沒上市，雖然預估在今年會正式上市。這個藥物正在等待被核准使用於治療及預防停經後骨質疏鬆症，以及用於預防接受芳香酶抑制劑乳癌病患或接受雄性激素去除治療之攝護腺癌患者的骨質流失。另一個後期研發的適應症是治療乳癌或攝護腺癌病患的骨轉移。對於大部分適應症，該藥物將會對抗雙磷酸鹽藥物，但是denosumab是該類別第一個藥物，這個類別是直接對抗RANKL的單株抗體，RANKL是骨骼更替的關鍵調控物質。
　　
　　【大部分病患都有反應】
　　這項研究由來自澳洲維多利亞東墨爾本Peter MacCallum癌症中心的David Thomas博士、FRACP與其美國、法國的同事們，還有來自Amgen的研究者們一起進行，該公司贊助這項研究。
　　
　　總共從8家中心收納了37位病患，但是有2位病患沒有足夠的病理學或放射學數據供療效評估。所有病患都罹患再發性或無法切除的骨骼巨細胞腫瘤，最常發生的位置在骨盆腔、肺部與下肢。
　　
　　所有病患每個月都接受denosumab 120 mg皮下注射一次（在第一個月時，於第8天、15天投予速效劑量）。
　　
　　主要試驗終點是腫瘤反應，定義為至少90%巨大細胞被清除，或是標的病灶沒有放射線攝影上的惡化達25週。研究者們報告，35位可評估病患中總共有30位（86%）達到試驗終點。
　　
　　Thomas博士與其同事們表示，其中20位病患有病理檢查結果，且這些病患的巨細胞腫瘤都完全或將近完全清除。15位病患有放射線攝影檢驗結果，這些病患中有10位疾病未惡化或疾病穩定；在某些病例觀察到客觀部分反應。這些觀察結果與這些研究者們臨床好處的報告相對應，例如降低疼痛、減少止痛藥物需求、功能、活動力改善，以及骨骼復原程度。
　　
　　大部分病患報告有不良反應（37位中有33位），最常見的是肢體疼痛（共7位）或背痛（共4位）、還有頭痛（共4位）。
　　
　　研究者們的結論是，這些結果顯示，denosumab在作為治療藥物上，具有對抗骨骼巨細胞腫瘤的活性。
　　
　　他們表示，目前這項研究的限制包括樣本數目太小、追蹤時間不長、以及單一組別設計。
　　
　　根據主編們表示，這些病患的差異以及較小的樣本數目並沒有使這項結果降級，因為這項研究族群正確地代表需要額外全身性治療、發生併發症的病患。
　　
　　他們解釋，但是仍然有許多問題需要釐清，包括牽涉到的作用機轉，與所需之治療療程。1位收納到這項研究的病患，在停藥後腫瘤再度惡化。他們寫到，這提出了一個問題，抑制效果是否只是暫時的，以及需要治療多久才能達到長期或是確切的效果。
　　
　　他們的結論是，前瞻性隨機分派研究收納更大的樣本數目，且追蹤至少2年以上將是必須的。
　　
　　這項研究由Amgen贊助，該公司是denosumab的製造廠商。Thomas醫師表示接受Amgen的顧問費用，以及諾華與輝瑞藥廠的研究經費。其中2位共同作者表示與藥廠有不同的資金往來，且有6位共同作者受雇於Amgen公司，詳細內容記載於文章中。主編們表示已無相關資金上的往來。


Denosumab "Promising" in Treatment of Giant Cell Tumor of Bone

By Zosia Chustecka
Medscape Medical News

February 11, 2010 — The novel biologic agent denosumab (Amgen) could offer a breakthrough in the treatment of the rare giant cell tumor of bone, suggests an editorial published online February?10 in The Lancet Oncology. It accompanies the publication of a small open study, which reports that the drug produced a tumor response in 30 of 35 patients (86%).

"To our knowledge, this is the first report that clearly shows a promising systemic treatment option for this rare type of tumor," write the editorialists, Maurice Balke, MD, and Jendrik Hardes, MD, from the Department of Trauma and Orthopedic Surgery at the University of Witten-Herdecke in Cologne, Germany. There have been reports of beneficial effects with bisphosphonates, but no successive prospective trials, they add.

The current treatment for giant cell tumor of bone is surgery, the editorialists point out. "If done thoroughly, the patient may be cured in up to 90% of cases."

But there are some cases of atypical giant cell tumor of bone with multiple local recurrences, multicentricity, pulmonary metastases, or lesions that are impossible to remove surgically without causing substantial morbidity, they continue.

"Surgery that causes major functional deficits is hardly justifiable for a lesion that is typically benign," but until now, promising alternatives have been lacking. "Hopefully, this will change," they write. "This excellent study?.?.?. might change clinical practice in the treatment of complicated giant cell tumor of bone."

Denosumab is not currently marketed, although a launch is expected this year. It is awaiting approval for use in the treatment and prevention of postmenopausal osteoporosis, and for the prevention of bone loss in breast cancer patients receiving aromatase inhibitors and in prostate cancer patients receiving androgen-deprivation therapy. Another indication in late development is the treatment of bone metastases in patients with breast and prostate cancer. For most of these indications, the drug would be competing against bisphosphonates, but denosumab is a "first in its class" product — a monoclonal antibody directed against RANKL, a key mediator in bone turnover.

Majority of Patients Responded

The study was conducted by David Thomas, FRACP, PhD, from the Peter MacCallum Cancer Center in East Melbourne, Victoria, Australia, and colleagues in the United States and France, as well as researchers from Amgen, which funded the trial.

A total of 37 patients at 8 centers were enrolled, but 2 patients had insufficient histology or radiology data for efficacy assessment. All patients had recurrent or unresectable giant cell tumor of bone, and the most common sites for lesions were the pelvis, lungs, and lower extremities.

All patients were treated with denosumab 120?mg subcutaneously once a month (after loading doses on days?8 and 15 of the first month).

The primary end point was tumor response, defined as the elimination of at least 90% of giant cells or no radiologic progression of the target lesions up to week?25. This was seen in 30 of the 35 evaluable patients (86%), the researchers report.

Histology results were available for 20 patients, and all of these showed a complete or near complete elimination of giant cells. Radiologic results were available for 15 patients, and 10 of these showed a lack of progression or stable disease; in some cases, objective partial responses were observed. These observations correlate with reports of clinical benefit by the investigators, such as reductions in pain requiring less analgesia and improvements in function, mobility, and bone repair, Dr. Thomas and colleagues note.

Adverse events were reported by most patients (33 of 37), most frequently pain in an extremity (n?= 7) or the back (n?= 4) and headache (n?= 4).

The results suggest that denosumab has "activity as a therapeutic agent" for giant cell tumor of bone, the researchers conclude.

Limitations of the current study are the fact that the sample size was small, the duration was short, and it was a single-group design, they note.

The small sample size and the heterogeneity of these patients "does not downgrade the results," according to the editorialists, "because the study population accurately represents patients with complications who are in need of additional systemic therapy."

But several issues remain to be addressed, including the mechanism of action involved and the duration of therapy needed, they explain. In 1 patient enrolled in the trial, tumor progression recurred after the drug was discontinued. "This raises the question of whether the inhibitory effect is only temporary and how long treatment must continue until a long-term or definitive effect is achieved," they write.

Prospective randomized trials with a high enrolment and a follow-up of at least 2 years will be necessary, they conclude.

The study was sponsored by Amgen, the manufacturer of denosumab. Dr. Thomas reports receiving consulting fees from Amgen and research grants from Novartis and Pfizer. Two of his coauthors report relationships with a variety of pharmaceutical companies, and 6 of his coauthors are employees of Amgen, as detailed in the paper. The editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online February 10, 2010.