{{short description|Type of electromagnetic field therapy}} {{cs1 config|name-list-style=vanc}} {{about|a specific type of electric field therapy used for treatment of cancer|other uses of electromagnetic fields in medicine|Electromagnetic therapy}} {{Infobox medical intervention (new) | name = Alternating electric field therapy | synonym = Tumor treating fields | image = | caption = | alt = | pronounce = | specialty = oncology | synonyms = | ICD10 = | ICD9 = | ICD9unlinked = | CPT = | MeshID = | LOINC = | other_codes = | MedlinePlus = | eMedicine = }} '''Alternating electric field therapy''', sometimes called '''tumor treating fields''' ('''TTFields'''), is a type of electromagnetic field therapy using low-intensity, intermediate frequency electrical fields to treat cancer.<ref name=or>{{cite journal |last1=Rominiyi |first1=Ola |last2=Vanderlinden |first2=Aurelie |last3=Clenton |first3=Susan Jane |last4=Bridgewater |first4=Caroline |last5=Al-Tamimi |first5=Yahia |last6=Collis |first6=Spencer James |date=2020-11-04 |title=Tumour treating fields therapy for glioblastoma: current advances and future directions |journal=British Journal of Cancer|volume=124|issue=4|pages=697–709 |doi=10.1038/s41416-020-01136-5 |issn=1532-1827 |pmid=33144698 |pmc=7884384}}</ref><ref name=NCCN_CNS>{{cite web |url=http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf |title=NCCN Guidelines for CNS cancers |access-date=4 August 2013}}</ref><ref name=SemRadOnc2014>{{cite journal |last1=Kirkpatrick |first1=John |title=Recurrent Malignant Gliomas |journal=Seminars in Radiation Oncology |date=October 2014 |volume=24 |issue=4 |pages=289–298 |pmid=25219814 |doi=10.1016/j.semradonc.2014.06.006 |pmc=4522935}}</ref><ref name=SemOnc2014>{{cite journal |last1=Johnson |first1=Derek |title=Medical Management of High-Grade Astrocytoma: Current and Emerging Therapies|journal=Seminars in Oncology |date=August 2014 |volume=41 |issue=4 |pages=511–522|pmid=25173143|doi=10.1053/j.seminoncol.2014.06.010}}</ref> TTFields disrupt cell division by disrupting dipole alignment and inducing dielectrophoresis of critical molecules and organelles during mitosis.<ref name=":1">{{cite journal |last1=Tuszynski |first1=Jack A. |last2=Wenger |first2=Cornelia |last3=Friesen |first3=Douglas E. |last4=Preto |first4=Jordane |date=2016-11-12 |title=An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields |journal=International Journal of Environmental Research and Public Health |volume=13 |issue=11 |page=1128 |doi=10.3390/ijerph13111128 |issn=1660-4601 |pmc=5129338 |pmid=27845746 |doi-access=free }}</ref><ref name=":2">{{cite journal |vauthors=Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD |date=2018-01-15 |title=Tumor-Treating Fields: A Fourth Modality in Cancer Treatment |journal=Clinical Cancer Research |language=en |volume=24 |issue=2 |pages=266–275 |doi=10.1158/1078-0432.CCR-17-1117 |pmid=28765323 |s2cid=36674866 |issn=1078-0432|doi-access=free }}</ref><ref name=":3">{{cite journal |last1=Hottinger |first1=Andreas F. |last2=Pacheco |first2=Patricia |last3=Stupp |first3=Roger |date=October 2016 |title=Tumor treating fields: a novel treatment modality and its use in brain tumors |journal=Neuro-Oncology |volume=18 |issue=10 |pages=1338–1349 |doi=10.1093/neuonc/now182 |issn=1523-5866 |pmc=5035531 |pmid=27664860}}</ref> These anti-mitotic effects lead to cell death, slowing cancer growth.<ref name=":1" /><ref name=":2" /><ref name=":3" /> A TTField-treatment device manufactured by the Israeli company Novocure is approved in the United States and Europe for the treatment of newly diagnosed and recurrent glioblastoma, malignant pleural mesothelioma (MPM), and is undergoing clinical trials for several other tumor types.<ref name=CTGNovocure>{{cite web |title=ClinicalTrials.gov results-Novocure |url=https://clinicaltrials.gov/ct2/results?term=novocure&Search=Search |website=ClinicalTrials.gov |access-date=26 December 2014}}</ref><ref>{{cite web |title=Using Tumor Treating Fields to Combat Mesothelioma |url=https://www.asbestos.com/treatment/ttfields/ |access-date=2023-12-04 |website=Mesothelioma Center - Vital Services for Cancer Patients & Families |language=en}}</ref> Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.<ref name=NCCN_CNS/><ref name=Wick2016>{{cite journal |last1=Wick |first1=Wolfgang |title=TTFields: where does all the skepticism come from? |journal=Neuro-Oncology |date=25 February 2016 |volume=18 |issue=3 |pages=303–305 |doi=10.1093/neuonc/now012 |pmid=26917587 |pmc=4767251}}</ref> __TOC__ ==Mechanism== All living cells contain polar molecules and will respond to changes in electric fields.<ref name=":3" /> Alternating electric field therapy, or Tumor Treating Fields (TTFields) use insulated electrodes to apply very-low-intensity, intermediate-frequency alternating electrical fields to a target area containing cancerous cells.<ref name=":3" /> Polar molecules play a key role in cell division, making mitosis particularly susceptible to interference from outside electric fields. TTFields disrupt dipole alignment and induce dielectrophoresis during mitosis, killing proliferating cells.<ref name=":2"/><ref name="andal">{{cite book |url=http://www.juntadeandalucia.es/salud/servicios/contenidos/nuevaaetsa/up/AETSA_2012_17_4%20Glioblastoma.pdf |title=Tumor treating fields therapy (TTFields) for glioblastoma. A systematic review of the literature |vauthors=Calzón Fernández S, Llanos Méndez A |publisher=Agencia de Evaluación de Tecnologías Sanitarias de Andalucía |year=2013 |isbn=978-84-15600-12-1 |language=es |type=Systematic review}}</ref><ref>{{cite journal |vauthors=Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y |date=1 May 2004 |title=Disruption of Cancer Cell Replication by Alternating Electric Fields |journal=Cancer Research |volume=64 |issue=9 |pages=3288–3295 |pmid=15126372 |url=http://cancerres.aacrjournals.org/content/64/9/3288.full.pdf |doi=10.1158/0008-5472.CAN-04-0083 |archive-url=https://web.archive.org/web/20140802015518/http://cancerres.aacrjournals.org/content/64/9/3288.full.pdf |archive-date=2014-08-02}}</ref><ref name="PNAS2007">{{cite journal |vauthors=Kirson ED, Dbalý V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y |date=12 June 2007 |title=Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors |journal=PNAS |volume=104 |issue=24 |pages=10152–7 |bibcode=2007PNAS..10410152K |doi=10.1073/pnas.0702916104 |pmc=1886002 |pmid=17551011 |doi-access=free}}</ref><ref name="discovery">{{cite journal |last1=Mrugala |first1=Maciej M. |date=25 April 2013 |title=Advances and Challenges in the Treatment of Glioblastoma: A Clinician's Perspective |journal=Discovery Medicine |volume=15 |issue=83 |pages=221–230 |pmid=23636139 |url=http://www.discoverymedicine.com/Maciej-M-Mrugala/2013/04/25/advances-and-challenges-in-the-treatment-of-glioblastoma-a-clinicians-perspective/}}</ref><ref name="Swanson2016">{{cite journal |last1=Swanson |first1=K |display-authors=etal |date=2016 |title=An Overview of Alternating Electric Fields Therapy (NovoTTF Therapy) for the Treatment of Malignant Glioma. |journal=Current Neurology and Neuroscience Reports |volume=16 |issue=1 |page=8 |doi=10.1007/s11910-015-0606-5 |pmc=4703612 |pmid=26739692}}</ref> thumb|Dipole molecules, such as Septins, become unable to move as needed during mitosis when exposed to TTFields, resulting in cell death.<ref name=":4">{{cite journal |last1=Gera |first1=Nidhi |last2=Yang |first2=Aaron |last3=Holtzman |first3=Talia S. |last4=Lee |first4=Sze Xian |last5=Wong |first5=Eric T. |last6=Swanson |first6=Kenneth D. |date=2015 |title=Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit |journal=PLOS ONE |volume=10 |issue=5 |article-number=e0125269 |doi=10.1371/journal.pone.0125269 |issn=1932-6203 |pmc=4444126 |pmid=26010837 |bibcode=2015PLoSO..1025269G |doi-access=free }}</ref>
=== Dipole Alignment === Polar molecules critical to mitosis include α/β-tubulin and the mitotic septin heterotrimer.<ref name="Swanson2016"/> Tubulin is necessary for mitotic spindle formation during metaphase, while septins stabilize the cell during cytokinesis. When exposed to TTFields, these molecules align their dipole with the electric field, freezing them in one orientation. This prevents tubulin and septin molecules from moving to and binding where they are needed for successful cell division.<ref name=":4" /> This results in mitotic catastrophe, initiating cell death through apoptosis.<ref name=":4" /> Uneven chromosome splitting can also be a result of TTFields' effect on dipole alignment, resulting in daughter cells with abnormal chromosome numbers.<ref name=":3"/><ref name=":34">{{cite web |title=Tumor Treating Fields |url=https://xvivo.com/blog/tumor-treating-fields-animation/ |access-date=2023-11-21 |website=XVIVO Scientific Animation |date=February 2012 |language=en-US | vauthors = Astrachan M }}</ref> thumb|TTFields induce dielectrophoresis in mitotic cells<ref name=":3"/>
=== Dielectrophoresis === Cells that successfully complete metaphase are later susceptible to TTFields during telophase.<ref name=":3" /> At this stage in cell division, the cell takes on an hourglass shape as it prepares to divide in two. This results in a non-uniform electric field within the cell, with high field density at the cell's furrow. This causes polar molecules and organelles to migrate with the electric field toward the furrow.<ref name=":2"/><ref name=":3" /> This disrupts the cell's division and leads to cell death.
=== Optimization === In principle, this approach could be selective for cancer cells in regions of the body, such as the brain, where the majority of normal cells are non-proliferating.<ref name="andal"/> The frequency of the TTField can be adjusted between 100 and 300kHz to target cancer cells and avoid harming healthy cells.<ref name="PNAS2007"/><ref name=":34"/> Current research supports that cell size is inversely proportional to optimal TTField frequency.<ref name=":2"/><ref name=":3" /> TTFields can also be optimized by orienting two transducer arrays perpendicular to each other to maximize the amount of cells that will be affected. Cells divide in different orientations and are most affected by an electric field that is parallel to their direction of division (perpendicular to the mitotic plate).<ref name=":2" /><ref name=":3" /><ref name=":34" /> Clinicians determine where to place the transducer arrays to optimize treatment using software that analyzes tumor location and the patient's morphometry.<ref name=":2" />
=== Other Biological Effects === Emerging evidence suggests that alternating electric field therapy disrupts various biological processes,<ref name=or/> including DNA repair,<ref>{{cite journal |last1=Giladi |first1=Moshe |last2=Munster |first2=Mijal |last3=Schneiderman |first3=Rosa S. |last4=Voloshin |first4=Tali |last5=Porat |first5=Yaara |last6=Blat |first6=Roni |last7=Zielinska-Chomej |first7=Katarzyna |last8=Hååg |first8=Petra |last9=Bomzon |first9=Ze'ev |last10=Kirson |first10=Eilon D. |last11=Weinberg |first11=Uri |date=2017-12-29 |title=Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells |journal=Radiation Oncology |volume=12 |issue=1 |page=206 |doi=10.1186/s13014-017-0941-6 |issn=1748-717X |pmc=5747183 |pmid=29284495 |doi-access=free }}</ref><ref>{{cite journal |last1=Karanam |first1=Narasimha Kumar |last2=Ding |first2=Lianghao |last3=Aroumougame |first3=Asaithamby |last4=Story |first4=Michael D. |date=March 2020 |title=Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy |journal=Translational Research: The Journal of Laboratory and Clinical Medicine |volume=217 |pages=33–46 |doi=10.1016/j.trsl.2019.10.003 |issn=1878-1810 |pmid=31707040 |doi-access=free}}</ref> cell permeability<ref>{{cite journal |last1=Chang |first1=Edwin |last2=Patel |first2=Chirag B. |last3=Pohling |first3=Christoph |last4=Young |first4=Caroline |last5=Song |first5=Jonathan |last6=Flores |first6=Thomas Anthony |last7=Zeng |first7=Yitian |last8=Joubert |first8=Lydia-Marie |last9=Arami |first9=Hamed |last10=Natarajan |first10=Arutselvan |last11=Sinclair |first11=Robert |date=2018 |title=Tumor treating fields increases membrane permeability in glioblastoma cells |journal=Cell Death Discovery |volume=4 |page=113 |doi=10.1038/s41420-018-0130-x |issn=2058-7716 |pmc=6281619 |pmid=30534421}}</ref> and immunological responses,<ref>{{cite journal |last1=Kirson |first1=Eilon D. |last2=Giladi |first2=Moshe |last3=Gurvich |first3=Zoya |last4=Itzhaki |first4=Aviran |last5=Mordechovich |first5=Daniel |last6=Schneiderman |first6=Rosa S. |last7=Wasserman |first7=Yoram |last8=Ryffel |first8=Bernhard |last9=Goldsher |first9=Dorit |last10=Palti |first10=Yoram |date=2009 |title=Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs |journal=Clinical & Experimental Metastasis |volume=26 |issue=7 |pages=633–640 |doi=10.1007/s10585-009-9262-y |issn=1573-7276 |pmc=2776150 |pmid=19387848}}</ref> to elicit therapeutic effects. Greater mechanistic understanding of TTFields may pave the way for new, more effective TTFields-based therapeutic combinations in the future.<ref name=or/>
==Medical uses== {{medref|section|date=December 2023}} ===Recurrent glioblastoma=== The American National Comprehensive Cancer Network's official guidelines list TTFields as an option for the treatment of recurrent glioblastoma, but note substantial disagreement among the members of the expert panel making this recommendation.<ref name="NCCN_CNS" /> High-quality evidence for the efficacy of TTFields in oncology is limited. The first randomized clinical trial evaluating TTFields was published in November, 2014, and evaluated efficacy of this approach in patients with recurrent glioblastoma.<ref name="UpToDateRecGlioma_11_2014">{{cite web|last1= Batchelor|first1= Tracy|last2= Shih|first2= Helen|last3= Carter|first3= Bob|title= Management of recurrent high-grade gliomas|url= http://www.uptodate.com/contents/management-of-recurrent-high-grade-gliomas|website= UpToDate|access-date= 26 December 2014}}</ref> This trial was the primary basis for regulatory approval of NovoTTF-100A / Optune in the United States and Europe.<ref name="UpToDateRecGlioma_11_2014" /> In this study, patients with glioblastoma that had recurred after initial conventional therapy were randomized to treatment either with a TTFields device (NovoTTF-100A / Optune) or with their treating physician's choice of standard chemotherapy. Survival or response rate in this trial was approximately 6 months, and was not significantly better in the TTFields group than in the conventional therapy group. The results suggested that TTFields and standard chemotherapy might be equally beneficial to patients in this setting, but with different side-effect profiles.<ref name="andal" /><ref name="UpToDateRecGlioma_11_2014" /> Two earlier clinical studies had suggested a benefit of TTFields treatment in recurrent glioblastoma, but definitive conclusions could not be drawn due to their lack of randomized control-groups.<ref name="andal"/>
===Newly diagnosed glioblastoma=== Initial results of a Novocure-sponsored, phase-3, randomized clinical trial of TTFields in patients with newly diagnosed glioblastoma were reported in November, 2014,<ref name="NeroOncAbstrEF-14">{{cite journal|last1= Stupp|first1= Roger|last2= Wong|first2= Eric|last3= Scott|first3= Charles|last4= Taillibert|first4= Sophie|last5= Kanner|first5= Andrew|last6= Kesari|first6= Santosh|last7= Ram|first7= Zvi|title= Interim Analysis of the EF-14 Trial: A Prospective, Multi-center Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in Patients with Newly Diagnosed GBM (Abstract)|journal= Neuro-Oncology|volume= 16|issue= suppl 5|pages= v167|url= http://neuro-oncology.oxfordjournals.org/content/16/suppl_5/v167.2.full.pdf+html?sid=c6967345-012c-4a57-a543-24b9684f8e86|access-date= 26 December 2014|doi= 10.1093/neuonc/nou265.40|year= 2014|doi-access= free}}</ref> and published in December 2015.<ref name="Stupp2015">{{cite journal|last1= Stupp|first1= R|title= Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma|journal= JAMA|date= 15 December 2015|volume= 314|issue= 23|pages= 2535–43|doi= 10.1001/jama.2015.16669|pmid=26670971|display-authors=etal|doi-access= free}}</ref><ref name="Sampson2015">{{cite journal|last1= Sampson|first1= John H.|title= Alternating Electric Fields for the Treatment of Glioblastoma|journal= JAMA|date= 15 December 2015|volume= 314|issue= 23|pages= 2511–3|doi= 10.1001/jama.2015.16701|pmid= 26670969}}</ref> Interim analysis showed a statistically significant benefit in median survival for patients treated with TTFields plus conventional therapy (temozolomide, radiation, and surgery) versus patients treated with conventional therapy alone, a result which led the trial's independent data monitoring committee to recommend early study-termination. This was the first large-scale trial in a decade to show a survival benefit for patients with newly diagnosed glioblastoma.<ref name="Sampson2015" /> On the basis of these results, the FDA approved a modification of the trial protocol, allowing all patients on the trial to be offered TTFields.<ref name="Novocure_Trial_IDE_modification">{{cite web |title= Novocure Announces FDA Approval of an IDE Supplement Allowing All Control Patients in its Phase III Trial in Newly Diagnosed GBM to Cross Over to Receive Tumor Treating Fields |url= http://www.novocure.com/~/media/Files/N/Novocure/press-release/2014/201410_IDE_Supplement.pdf |access-date= 2014-12-26 |archive-url= https://web.archive.org/web/20141227184631/http://www.novocure.com/~/media/Files/N/Novocure/press-release/2014/201410_IDE_Supplement.pdf |archive-date= 2014-12-27 }}</ref> Potential methodological concerns in this trial included the lack of a "sham" control group, raising the possibility of a placebo effect, and the fact that patients receiving TTFields received more cycles of chemotherapy than control patients.<ref name="Sampson2015" /> This discrepancy might have been a result of improved health and survival in TTFields-treated patients, allowing for more cycles of chemotherapy, but also could have been due to conscious or unconscious bias on the part of clinical investigators.<ref name="Sampson2015" /> An expert clinical review called the preliminary results "encouraging".<ref name="UTDInitialTxGBM_11_2014"> {{cite web |last1= Batchelor|first1= Tracy |title= Initial postoperative therapy for glioblastoma and anaplastic astrocytoma |url= http://www.uptodate.com/contents/initial-postoperative-therapy-for-glioblastoma-and-anaplastic-astrocytoma |website= UpToDate|access-date= 26 December 2014 }} </ref>
==Medical device== A clinical TTFields device is manufactured by Novocure under the trade name Optune (formerly NovoTTF-100A), and is approved in the United States, Japan, Israel and multiple countries in Europe for the treatment of recurrent glioblastoma. These devices generate electromagnetic waves between 100 and 300 kHz. The devices can be used in conjunction with regular patterns of care for patients, but are only available in certain treatment centers, and require specific training and certification on the part of the prescribing physician.<ref name="discovery"/><ref name=UpToDateRecGlioma_11_2014/> When a TTFields device is used, electrodes resembling a kind of "electric hat"<ref name=forbes/> are placed onto a patient's shaved scalp. When not in use, the device's batteries are plugged into a power outlet to be re-charged.<ref name=forbes>{{cite web |last=Herper |first=Matthew |date=Apr 15, 2011 |title=Cancer-Fighting Electric Hat Proves We Live in the Future |url=https://www.forbes.com/sites/matthewherper/2011/04/15/cancer-fighting-electric-hat-proves-we-live-in-the-future/ |website=Forbes }}</ref>
=== Side effects === The adverse effects of TTFields include local skin rashes and irritation caused by prolonged electrode use.<ref name="PNAS2007" /><ref name=":3" /><ref name=":2" /> Compared with other cancer treatment methods, this effect is very minimal and tolerable for the patient.<ref name="PNAS2007" /> This irritation can be controlled with steroid creams and periodic breaks from treatment.<ref name=":3" />
== Regulatory approval == The NovoTTF-100A / Optune device was approved by the U.S. Food and Drug Administration (FDA) in April 2011 for the treatment of patients with recurrent glioblastoma, based on clinical trial evidence suggesting a benefit in this population. Because the evidence for therapeutic efficacy was not deemed conclusive, the device manufacturer was required to conduct additional clinical trials as a condition of device approval.<ref name=NovoTTF_FDA_approval>{{cite web|title=FDA approval letter - NovoTTF-100A System |url=https://www.accessdata.fda.gov/cdrh_docs/pdf10/p100034a.pdf|website=www.fda.gov|access-date=26 December 2014}}</ref> Critics suggested that pleas of cancer patients in the room of the FDA hearing swayed the opinions of many during the related FDA panel, and that approval was granted despite "huge misgivings on several points".<ref name=mdd>{{cite news |title=NovoCure Wins Nod from Panel despite Trial, Statistical Miscues |work=Medical Device Daily |date=21 March 2011 |url=http://www.highbeam.com/doc/1G1-251979971.html |via=Highbeam |archive-url=https://web.archive.org/web/20140610085733/http://www.highbeam.com/doc/1G1-251979971.html|archive-date=10 June 2014}}</ref>
Optune was approved by the FDA for newly diagnosed glioblastoma on Oct. 5, 2015,<ref>{{cite press release |date=October 5, 2015 |publisher=U.S. Food and Drug Administration |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465744.htm |title=FDA approves expanded indication for medical device to treat a form of brain cancer |archive-url=https://web.archive.org/web/20151008012814/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465744.htm |archive-date=2015-10-08}}</ref> as a result of randomized phase 3 trial results that reported a 3-month advantage in overall survival and progression-free survival when added to chemotherapy with temozolomide.<ref name=NeroOncAbstrEF-14/><ref name=Stupp2015/> In the US, Medicare covers treatment, as of February 2020.<ref name=The_Oxford_Communique>{{cite news |last1=Green |first1=Alexander |date=February 2020 |title=This Company Destroys Cancer Cells But With Electricity... Not Drugs Or Radiation |agency=The Oxford Communique}}</ref>
==Company== Novocure Ltd. (Nasdaq: NVCR) was founded in 2000. As of December 2020, Novocure Ltd. has over 1000 employees and makes hundreds of millions of dollars in annual sales. Israeli Professor Yoram Palti, professor of physiology and biophysics at the Israel Institute of Technology, is the company's founder and chief technology officer. Novocure Ltd. owns 145 patents.<ref name=The_Oxford_Communique/>
==See also== {{portal|Medicine}} *Angiogenesis inhibitors *Experimental cancer treatment *Pulsed electromagnetic field therapy
==References== {{reflist}}
==Further reading== * {{cite journal|doi=10.1111/nyas.12112|title=Tumor treating fields: A new frontier in cancer therapy|year=2013|last1=Davies |first1=Angela M. |last2=Weinberg |first2=Uri |last3=Palti |first3=Yoram |journal=Annals of the New York Academy of Sciences |volume=1291 |issue=1 |pages=86–95 |pmid=23659608 |bibcode=2013NYASA1291...86D |s2cid=33153055}}
==External links== * [https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm254480.htm Approval acknowledgement from FDA]{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}
Category:Angiogenesis inhibitors Category:Cancer treatments Category:Medical devices