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作者：Zosia Chustecka  
出處：WebMD醫學新聞

　　May 14, 2010 — 使用血管內皮細胞生長因子(VEGF)抑制劑的癌症病患，在治療期間應定期監測血壓，特別是第一個療程的時候。
　　
　　研究者在5月5日美國國家癌症研究院期刊(Journal of the National Cancer Institute)中提出建議，這些病患也需使用降血壓藥物來控制此類抗癌藥物引起的高血壓。
　　
　　作用在VEGF訊號路徑的藥物包括，bevacizumab (Avastin)、sorafenib (Nexavar)、sunitinib (Sutent)以及pazopanib (Votrient)。
　　
　　這些藥物已經在全球上市用於治療多種癌症，還有許多類似藥物正在進行最後階段的臨床研發，例如aflibercept、axitinib、cediranib、motesanib以及vandetanib。作者們指出，VEGF抑制劑用於癌症治療時可以挽救生命，但是，它們的作用機轉可能會導致心血管副作用、導致治療停止，甚至是致命的後遺症。
　　
　　作者們寫道，高血壓是所有此類藥物的副作用，有些案例的血壓是急遽升高。
　　
　　他們的報告詳列了一系列處置這種副作用的新建議，他們希望，這有助於更安全地引導、更廣泛地使用這些藥物。
　　
　　芝加哥大學醫學中心醫學助理教授Michael Maitland博士在聲明中表示，這篇文獻對於當今實務將有所影響。
　　
　　共同作者、芝加哥大學醫學中心高血壓疾病小組主任George Bakris醫師表示，這篇文獻對於一般指引做出了有發展性的努力，成功處置病患情況，以確保達到理想結果。
　　
　　這篇報告的作者來自心血管毒性小組，由國家癌症研究院研發藥物指導委員會血管新生工作小組召集。
　　
　　麻州波士頓哈佛醫學院、達那-法柏癌症研究治療中心的Toni Choueiri醫師表示，在VEGF標靶藥物之心血管與高血壓影響的研究領域中，這是一個很有用且有眼光的研究。
　　
　　Choueiri醫師並未參與提出新版建議，但是他曾經發表VEGF抑制劑的心血管副作用，Medscape Oncology曾經加以報導。
　　
　　他認為，多數腫瘤科醫師普遍認為血壓升高是這類藥物的副作用，但是，他不認為這個情況有被積極治療，他也看過醫師因為血壓的影響、但未試圖加以處置之下即放棄可能有用的治療藥物。
　　
　　Choueiri醫師指出，腫瘤科醫師應儘可能遵守這些建議。
　　
　　【處置步驟】
　　作者們解釋，這篇報告聚焦在血壓升高，因為這是抗癌藥物的所有副作用中，最常見且最容易處理的問題，其他副作用包括出血、血栓、腎毒性以及心臟毒性。
　　
　　在他們對於使用VEGF抑制劑之癌症病患的血壓處置建議中，該小組建議在開始治療前進行心血管併發症的正式風險評估，包括：
　　* 至少在2個不同情況下測量血壓，記住可能會有白袍高血壓。
　　* 瞭解癌症病患是否已經有高血壓，若有，則在開始進行治療前加以處置。
　　* 治療期間主動監測血壓，在第一個療程時要增加監測頻次，特別是預期血壓會急速升高時。
　　* 血壓目標值為140/90 mm Hg，不過可能因為病患原本的情況而更低，例如糖尿病和/或慢性腎臟病。
　　
　　該小組也建議，如果腫瘤科醫師或主治醫師對於達到或維持血壓目標有所困難，應照會當地的血壓專科醫師(或心臟科、腎臟科、內分泌科醫師)。
　　
　　在Medscape Oncology的訪問中，Maitland醫師表示，這類合作照護是關鍵，因為癌症病患服用藥物引起高血壓的處置可能相當複雜，尤其這些病患可能還有接受化療、本身有其他心血管風險，如腎臟病或糖尿病。他指出，腫瘤科醫師在不擅長的領域中應找心血管方面的同事幫助。
　　
　　他指出，許多癌症病患可以耐受略微上升的血壓，相較於這些病患可能會發生的其他事情，許多腫瘤科醫師可能也不會擔心略為增加的血壓。重點不在於單就血壓上升這件事情，而是相關的所有事情，特別是病患的心血管風險資料。他表示，這是這篇報告的主要重點之一，在開立這些藥物之前，必須評估癌症病患的心血管風險因素。
　　
　　Maitland醫師表示，這些藥物升高的血壓值大約在8 -10 mm Hg(收縮壓和舒張壓)，這個幅度大於一般降血壓藥物可以降低的程度，不過，血壓升高程度相當有差異性，有些病患並沒有這類影響，有些病患上升超過25 mm Hg。
　　
　　Maitland醫師指出，主要訊息是，維持血壓在140/90 mm Hg之下，糖尿病或慢性腎臟病患甚至要更低，因為許多癌症病患年事已高，因此有較高的高血壓風險，可能在開始使用VEGF抑制劑治療之前，血壓就超過前述目標值了。
　　
　　在該報告中，作者們認為，目前對接受VEGF抑制劑的癌症病患進行特定的血壓處置有一些挑戰，但是，他們也強調，這是良好醫療照護的自然延伸。
　　
　　Maitland醫師解釋，如果病患有高血壓，不能因為有末期癌症就被等閒視之，我們已經知道，忽視癌症病患的共病症會對他們的長期存活與癌症分期有相當大的風險。
　　
　　作者們指出，在這些病患中，維持血壓在安全範圍的最簡單方式是，每週由診間護士測量或者居家測量血壓。
　　
　　使用VEGF抑制劑治療期間任何突發的高血壓，都可以使用任何一種降血壓藥物(thiazide類利尿劑、乙型阻斷劑、鈣離子通道阻斷劑、血管收縮素轉換酶[ACE]抑制劑、以及血管收縮素受體阻斷劑)控制。作者們指出，這些類別的每個藥物都可以成功控制VEGF抑制劑治療引起的高血壓，至於哪種藥物的成功控制率優於另一種，則還有待確認。
　　
　　該篇報告總結指出，處方這些藥物給癌症病患時需記住重點；舉例而言，ACE抑制劑應避免用於使用cisplatin和pemetrexed等需要腎清除率的化療病患。最後，該小組指出，VEGF抑制劑引起的血壓上升會在停藥之後消失，所以，開方的降血壓藥物也需隨著停藥或減量。
　　
　　【作用機轉】
　　Maitland醫師表示，有關VEGF抑制劑為何會引起血壓上升的理論有兩種，VEGF訊號直接調節一氧化氮合成酶的酵素功能，這些藥物對於減少一氧化氮產生有立即效果、收縮小血管、引起血壓立即上升，實際上，Maitland醫師報告指出，我們有一些在服用這些藥物的第一天就出現血壓上升的例子。
　　
　　也有研究顯示，在服用bevacizumab的病患中，皮膚切片中的微血管流失、稀少，這得花上幾天或幾週，他指出，有些病患在服用這些藥物一週以上才發生血壓升高。
　　
　　Maitland醫師表示，可能這兩種情況都存在；這些理論不衝突，我們也認為，所有這些藥物對血壓的效果相似，但是沒有人真的暸解。
　　
　　Maitland醫師報告接受來自Bayer和Genentech的研究資金，多名共同作者報告相關的財務關係，詳載於報告中。


New Recommendations for Monitoring BP in Cancer Patients on VEGF inhibitors

By Zosia Chustecka
Medscape Medical News

May 14, 2010 — Cancer patients being treated with drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway should have their blood pressure (BP) monitored regularly throughout treatment, particularly during the first cycle of therapy.

These patients might also need treatment with antihypertensive agents for the BP elevations that occur as an adverse effect of these anticancer drugs, say the authors of a new set of recommendations published in the May?5 issue of the Journal of the National Cancer Institute.

Drugs acting on the VEGF signaling pathway include bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), and pazopanib (Votrient).

These drugs are already marketed worldwide for use in the treatment of variety of different cancers, but there are several similar drugs in the late stages of clinical development, including aflibercept, axitinib, cediranib, motesanib, and vandetanib.

The VEGF inhibitors are potentially life-saving in the treatment of cancer, the authors note, but their mechanism of action can lead to cardiovascular adverse effects, which in some cases have led to treatment cessation and even life-threatening consequences.

Hypertension has been reported as an adverse event of all of these drugs, and in some cases the BP elevation has been "dramatic," the authors write.

Their paper details a new set of recommendations to deal with this adverse event, and they hope it will "guide safer, more expansive use of these drugs."

This pape should [have an] impact [on] practice today.

"This paper should [have an] impact [on] practice today," Michael Maitland, MD, PhD, assistant professor of medicine at the University of Chicago Medical Center, in Illinois, said in a statement.

Coauthor George Bakris, MD, director of the Hypertensive Diseases Unit at the Chicago University Medical Center, described the paper as a "seminal effort to provide some kind of general guidance?.?.?. [on] how to successfully manage patients to make sure the outcome is ideal across the board."

The authors of the paper made up the Cardiovascular Toxicities Panel, convened by the Angiogenesis Task Force of the Investigational Drug Steering Committee of the National Cancer Institute.

"This is a very useful and insightful paper in a rapidly growing field characterized by hypertension and other cardiovascular effects from the VEGF-targeted agents," said Toni Choueiri, MD, from the Dana-Farber Cancer Institute at Harvard Medical School in Boston, Massachusetts.

I have also seen physicians giving up on potentially beneficial drugs because of blood pressure.

Dr. Choueiri was not involved in drawing up the new recommendations, but he has reported on the cardiovascular adverse effects of VEGF inhibitors, as previously reported by Medscape Oncology.

"I think that blood pressure elevation is well recognized as a side effect of these drugs by most oncologists, but I do not think it is being treated aggressively," he said. "I have also seen physicians giving up on potentially beneficial drugs because of blood pressure, despite minimal efforts to control it."

"Oncologists should follow, as closely as possible, these recommendations," Dr. Choueiri added.

Steps for Management

The report focuses on BP elevation because it is "the most common and the easiest to address" of all the adverse effects reported for this groups of anticancer drugs, the authors explain. Others adverse effects include hemorrhage, thrombosis, nephrotoxicity, and cardiac toxic effects.

In their recommendations for BP management in cancer patients taking VEGF inhibitors, the group suggests a formal risk assessment of cardiovascular complications before starting therapy. This should include:

BP measurement on at least 2 separate occasions, bearing in mind the potential for "white coat hypertension."
Recognition that preexisting hypertension is common in cancer patients, and addressing it before initiating therapy.
Active monitoring of BP throughout treatment, with more frequent assessments during the first cycles of therapy, when the bulk of the BP elevation is expected to occur.
A maximum hypertension goal of 140/90?mm?Hg, although this would be lower for patients with preexisting conditions, such as diabetes and/or chronic kidney disease.
The panel also suggests that if at any time the oncologist or treating physician has any difficulty reaching or maintaining this BP goal, there should be a prompt consultation with the local hypertension specialist (or cardiologist, nephrologist, or endocrinologist).

In an interview with Medscape Oncology, Dr. Maitland said that this collaboration is key because the management of drug-induced hypertension in cancer patients who are probably also on chemotherapy can be rather complicated, especially if the patient has other cardiovascular risk factors, such as kidney disease or diabetes. Oncologists who are "out of their comfort zone" should reach out to cardiovascular colleagues for help, he added.

Many cancer patients are able to tolerate modest elevations in BP, and many oncologists might not be concerned about modest elevations, with everything else that is happening in these patients, he noted. It is not the jump in BP alone that is important, it is how it relates to everything that has gone before, particularly in relation to a patient's cardiovascular risk profile. "That is one of the main points of the paper — that cancer patients need to be assessed for cardiovascular risk factors before these drugs are prescribed," he said.

The average elevation in BP seen with these drugs is about 8 to 10?mm?Hg, both diastolic and systolic, Dr. Maitland said. This is a greater magnitude than can be lowered by standard antihypertensive drugs, he added. However, BP elevation is also highly variable, with some patients not showing much of an effect, and some showing a jump of more than 25?mm?Hg.

The main message is to keep BP below 140/90?mm?Hg, and even lower for patients with diabetes or chronic kidney disease, Dr. Maitland pointed out. Because many patients with cancer are elderly, and therefore at higher risk for hypertension, BP might be above this target even before treatment with VEGF inhibitors is started.

In the paper, the authors recognize that implementing a specific approach to BP management in cancer patients receiving VEGF inhibitor drugs "presents logistical challenges," but they also emphasize that this process is "a natural extension of good general medical care."

"If a patient is hypertensive, a physician should not dismiss that as irrelevant just because they have advanced cancer," Dr. Maitland explained. "We already know that ignoring comorbidities in a cancer patient can generate as much risk for their long-term survival as the stage of cancer."

In these patients, the easiest approach to maintaining BP within a safe range might be weekly office nursing visits or home BP monitoring, the authors note.

Any emergent hypertension that develops during VEGF inhibitor therapy can be controlled by any one of a variety of antihypertensive drugs (thiazide diuretics, beta blockers, calcium-channel antagonists, angiotensin-converting-enzyme [ACE] inhibitors, and angiotensin-receptor antagonists). Each of these classes has been used successfully to control hypertension resulting from VEGF inhibitor therapy, the authors note, and "whether any one agent is superior to another in the successful control rates remains to be determined."

The paper summarizes points that need to be kept in mind when prescribing these agents to cancer patients; for instance, ACE inhibitors should be avoided in patients who are on chemotherapy that requires renal clearance, such as cisplatin and pemetrexed.

Finally, the panel notes that the BP elevation caused by VEGF inhibitors will dissipate when the drug is discontinued, so physicians need to anticipate discontinuing or reducing the dose of any antihypertensive drug that has been prescribed.

Mechanism of Action

There are 2 theories as to why VEGF inhibitor anticancer drugs increase hypertension, Dr. Maitland said. VEGF signaling directly regulates the enzyme functioning of nitric oxide synthetase, and these drugs have the immediate effect of reducing nitric oxide production and constriction of small blood vessels, which causes an immediate rise in BP. Indeed, Dr. Maitland reported, "we have instances where BP is elevated in the first day of taking these drugs."

There is also work showing that in patients taking bevacizumab, there is a loss of capillaries in skin biopsies, suggesting rarefaction, which would take days and weeks. Some patients develop BP elevations more than a week after taking these drugs, he added.

It might be that both processes are underway; these theories are not competing, Dr. Maitland said. "We also think that all of these drugs are similar [in their effects on BP], but nobody really knows," he added.

Dr. Maitland reports receiving research funding from Bayer and Genentech. Several of his coauthors report relevant financial relationships, which are detailed in the paper.

J Nat Cancer Inst. 2010;102;596-604.