Tap chi Tai MOi Hong Viet Nam - Volume (59-20). N°2- April, 2014
MOT SO TIEN BO TRONG HOA TRI LIEU UNG THir HA HONG THANH QUAN
Bim Trpng Nghia*, Trin Bang Khoa*, Nguyin Binh Phiic**
TOM TAT
Diiu tri ung thu hg hong thanh qudn vol quan diem tru&c ddy la da mo thuc gomfphdu trt, xg trl, hoa trl. Vdi hiiu biit Men nay vi sinh hoc phdn tu thi hoa trl vd lleuphd^ nhdm tning dich ngdy cdng duac dp dung dd mang lgi hieu qud cao. Hod tri vd lieu phdp nhdm trung dich trong ung thu hg hong thanh qudn gigi dogn muon co the dugrc dp dung tru&c^ (tdn bo trg) hoac ddng thoi vol xg trl, dp dung sgu (bd trg). Hoa trl trudc coi nhu Id mot phdn cua bdo ton ca quan vd tdng hieu qud dieu trl, tdng chdt lugng song cho ngudl benh.
Tu khoa : Ung thu hg hong thanh qudn SUMMARY
Treatment of pharynx- laryngeal cancer throat down to the previous point Is the multi-model including: surgical therapy, radiation therapy, chemotherapy. With the current knowledge about the molecular biology, chemotherapy and targeted therapy is a goals Increasingly taken have high efficiency. Chemotherapy and targeted therapy on target in the lower pharynx larynx cancer late stage can be applied before or concurrently with radiotherapy, after application. Before chemotherapy Is considered as a part of conservation agencies and increasing to the effectiveness oftreatment, increased quality of life for patients.
Keys Words: Pharynx- laryngeal cancer
1. DAT V A N D E quan tam, nghien ciiu. Nhilu thudc mdi Phlu thuat va xa tri la nhiJng phuang *"'"= '" ' ' " ™ ^^^ '^^"8 '^'^^"8 ™8 thu phap chinh dieu tri benh nhan ung thu tS °84y cang hieu qua va tac dung phu duoc bao vay vimg diu c6. Hoa tri h?n'^^e ten miic tot da, cimg vol nhiSu phac (Chemotherapy) la phuang phap sit dung ^° P''"' ^^ *"°<= '=° 1^?" 1"* <=^° <''"' cac thu6c gay dpc tS bao nhim tieu diet cac """J *^^ f * ^ " ^ *'= •"?" ''^° '™8 '<"' tl bao ac tinh trong co thl nguai benh ung *'*"'' ™ * ^
thu. Nhiing bao cao gan day ve dieu tri hoa Voi hon 60 nam duoc su dung trong "'^^ * ° ™S * " . ' ' » '^''"8, thanh quto giai lam sang, viec ap dung hoa tri diiu tri ung ^°^ " i " ' " ^^ .'^™8 dinh dugc vai tro cua thu tren thl giai da co nbilu tiln bo dang ^°^ <=''^' ™ * ^ ' ^ """y ^Si chi djnh phau kl va ngay cang duac nhilu nha khoa hoc *•?»' '^™ '*™8 ™S thu giai doan tien tnen. Hoa tn la mot phan cua didu tri CO
•Benh Vien Ung Budu Ha Noi ''*°' ''9'' "•' " ' " "^ * ^ ''"«"^ *P '"^Ig tmcrc
••Tniong Dai Hoc YHa Noi (t™ bo tro) hoac Cung thai gian (h6a x?
Nlian bai 20/3. Duy?t in 30/3/2014 62
Tgp chi Tai Mui Hgng Vidt Nam - Volume (59-20). N°2- April, 2014
dong thdi) vdi xa tri, dp dung sau (bo trg).
Cdc tac dung phu cua hod tri cd khuynh hudng ban chfi kfit hgp.[l]
2. HOA XA TRI DONG THCH Hda xa tri ddng thdi cdi thien kifim soat tai chd/tai viing va ty lfi sdng them.
Ngoai ra, kfit hgp hda tri lieu vdi xa tn ndng cao ty le bdo tdn ca quan . Phan tich meta cua Pignon cho thdy hda xa ddng thdi cd cisplatin tang toi da lgi ich cho benh nhan ung thu ha hgng thanh quan khi su dung. Id lira chgn hang dau trong difiu tri trifit can [2]. Don cisplatin Id hda chdt gay dgc tfi bao dugc lua chgn cho hda xa dfing thoi. Cisplatin boat ddng bang cdch hinh thdnh ben trong va lien sgi cdu tnic DNA, ddn dfin uc chfi tfing hgp DNA. Cisplatin dnh hudng tifim tang vdi xa tri bdng cdch lie chl viec sua chiia cac thifit hai gay chfit ciia tfi bdo, bdi co chfi tuong ddng vd khdng tuong ddng siia chiia DNA .
Thuc tfi hifiu ling nay khdng phdi la d ^ hieu cho khdi u, nhung dugc ho trg boi tdng dpc tinh cdp tinh thay trong phac dd hda xa ddng thdi. Hai trong sd cac nghien ciiu chiing minh lgi ich ciia hda xa dfing thoi sd dung cisplatin 100 mg/m^ vao cdc ngay 1, 21, 43 cua hda xa dfing thdi cho thdy tdng ddc tinh dang kfi cho nhdm hda xa dfing thdi [3] Chi cd 70-80% benh nhdn theo dufii dii ba chu ky hda tri. Vi vdy cdc trung tdm ung thu su dung mdt Uch trinh it dpc hai voi hai chu ky cisplatin, cisplatin lifiu thip hdng tudn hoac su dung carboplatin thay thfi [4] dfi nang cao svr tuan thii cda b?nh nhdn. Cac phac dd kfit hgp cua paclitaxel va carboplatin hdng tudn, 5- flurouracil (5-FU) va carboplatin vd 5 FU va mitomycin C la nhung each ket hgp khdc trong difiu tri da md thiic [5]
Trong mgt nghifin ciiu pha II gdn ddy
da bao cdo, hda chdt ddng mach lieu cao cisplatin va xa tri dfing thdi (RADPLAT) dugc sii dung dfi difiu tri 67 benh nhdn ung thu ha hpng thanh qudn giai doan IV.
RADPLAT Ufin quan dfin vific dua cisplatin true tifip vdo khdi u bdng dudng ddng mach dfi giam thifiu nhimg tac ddng ciia thufic dfin he thfing hoac bang cdch sii dung tmyfin tmh mach thiosulfat natri ddng thdi, mdt thudc trung hda cisplatin. Viec su dung cac tdc nhdn trung hda se lam tang lieu thap hang tudn cua cisplatin dfin nam ldn so vdi lifiu chudn. Phdc dd RADPLAT thdy la chdp nhan dugc vdi sdng them toan bg 2 nam Id 63% . Sir chdp nhdn phdc dfi nay bi ban chfi Id do cac vdn dfi ky thudt vdi dua thudc bdng duotig ddng mach. [6]
Cac nghifin cuu ciia EORTC va RTO 95-01 da cho thdy cai thifin sdng thfim khfing benh, ty lfi kifim sodt tai cho/tai vung va sdng them todn bd (EORTC) d bfinh nhan cd nguy co cao nhdn hda xa ddng thdi tifip sau la phdu thudt triet de. Cd hai thu nghifim nay dfiu su dung lieu phdp hda tri bdng cisplatin. Bfinh nhan lan tran vd hach lien quan dfin cac hach bach huyet va difin phau thudt duang tinh dugc nhdn lifiu tdi da hda xa ddng thdi sau phdu thudt. Vd hda xa ddng thdi hau phlu hifin Id tieu chudn vfi chdm sdc cho cdc benh nhdn cd nguy co cao ma dugc dinh nghia tu cac nghien ciiu nay [7].
3. HOA TRI LIEU TAN BO TRQ Trong ung thu ha hgng, thanh qudn, difiu tri hda chdt tan bd trg cdn phdi hgp nhifiu phucmg phap nhu xa trj, phdu thudt nhdm dat hifiu qud tfii da. Phau thuat cd thfi cit mdt phdn hay toan bd ha hgng, thanh qudn va nao vet hach sau dd difiu tri xa tri so voi difiu tri hod chdt trudc sau do tiep tuc tia xa. Bao cdo gdn ddy cho thdy hai chifin
Tap chi Tai MQi Hgng Vifit Nam - Volume (59-20). N°2-April, 2014
lugc nay tuong duong nhau. Cho tdi nay, khdng cd su khac biet dang ke ve thdi gian sdng thfim d cac nghien cuu nay. Kfit hgp ca phdu thuat va tia xa cd ty lfi kifim soat cao hon so vdi dung mdt phuang phap [8],Tuy vay sau hoa chat tdn cfing khong phai tat cd cdc bfinh nhan ung thu ha hpng, thanh quan dfiu can phdu thuat. Lgi ich cua phau thuat la ddnh gia dap iing md bfinh hgc tao difiu kifin tdt hon cho hoa chdt sau phlu thudt va giam lifiu tia xa, nhung trong difiu tri hoa chat tan bd trg kfit hgp tia xa bdo tdn dupc thanh quan, ha hgng dac bifit la gigng ndi, ndng cao chat lugng cupc sfing cho bfinh nhan. Ly do co ban viec su dung hda tri lieu tan bd trg la phan phdi thudc cd thfi se tdt hon trong cac khdi u khdng thfi dieu tri cd nhieu mach mdu tan tao, bfinh cd the giam di vfi giai doan tnrdc khi dieu tri triet can va cac vi di can cd thfi la dich de nham tdi. Hda tri lieu tdn bd trg dugc sd dung trong thuc hanh lam sang va dugc cho la cd lgi thfi cho vific giam ty lfi di can xa, tang bao tdn co quan va tang ty lfi sdng them [9] . Su kfit hgp cua cisplatin (75-jOOmg/y ) va 5-FU (750-1000 mg/m^
) mdi ba tudn la phac do (PF) thudng dugc su dung nhat dfi difiu tri tan bd trg. Phdc dd PF cai thien song them 5 nam 5% . Da cd ba thu nghiem ngdu nhifin thfim taxanes vao phuang phap tifip can tifiu chudn trfin dieu tri tuan tu.
Paclitaxel la mfit hda chdt da dugc thu nghifim pha 11, pha 111 vdi cd mdu nghifin ciiu ldn. Trong mpt nghifin cuu pha III so sanh paclitaxel/cisplatin vdi cisplatin/5-FU, kfit qua cho thdy khfing cd su khac bifit trong ti lfi dap iing hoac sdng thfim, nhung su ket hgp vdi paclitaxel uu vifit han nhifiu khi phdn tich chdt lugng cudc sdng.
Docetaxel da dugc thu nghifim trong cac each kfit hgp khdc nhau, vdi xa tri, hoac tan
bd trg trudc phdu thuat. Mpt trong nhung phdc do dugc su dung manh nhdt Id docetaxel kfit hgp vdi cisplatin (cd hodc khdng cd 5-FU). Mac du ddc tinh vdi he tao huyfit ldn, song phiic hgp nay da dugc nghien ciiu pha II vdi kfit qua han 90% co dap ling, trong dd 40-60% Id dap iing hodn toan. Nghien ciiu ngdu nhifin pha ffl so sanh docetaxel vdi cisplatin vd cisplatin vdi 5 FU cho cac hrudng hgp HNSCC tdi phdt hoac di can Men nay dang d giai doan cufii cung va hy vgng kfit qua se khd quan. Trong thu nghifim ngau nhifin cua Hitt, paclitaxel da dugc bo sung vdi cisplatin va 5 FU d mpt nhdm nghifin ciiu [10]; mac du ty le dap ling tdt hon trong thd nghiem nay khdng cd sir khac bifit, song trong song them toan bp da thdy rd su khdc bifit (51%
so vdi 43%, p = 0,063). Trong hai nghifin cuu bao cao gdn day (EORTC24971/TAX 323 va TAX 324), docetaxel da dugc them vdi cisplatin vd 5-FU (TPF) d thu nghiem de difiu tri tan bd trg [11] . Nghien cuu cua Vermorken cho thdy lgi ich sfing thfim cho nhdm cd docetaxel, nhung sdng thfim 2 nam toan bd (43%) lai thdp hon trong nghifin ciiu su dung phuong phap tudn tir[12]. Tuy nhifin, nghien ciiu nay chi bao gdm bfinh nhan khdng mfi va hda xa tri ddng thai khdng dugc su dung. Vi vay khd nit ra kfit luan ndo tir nghifin ciiu nay lien quan dfin lgi ich vdi cac bfinh nhan su dung taxanes theo phuong phdp tudn tu cho ung thu ha hpng giai doan mudn. Posner thfi hifin khac bifit thdng kfi dang kfi trong sdng them 2 nam ia 68% cho nhom TPF so vdi 55% cho nhdm PF sd dung phuong phap tudn tu trong ung thu ddu cfi giai doan mugn [13]. Tdm lai, tu nhung du lieu nay cho thdy hda tri tdn bd trg vdi phac dfi 2-3 thudc se ngay cang dugc su dung trong tuang lai.
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Tap chl Tai MOi Hong Vidt Nam - V o l u m e (59-20). N°2- April. 2014
Vific su dung hda tri lieu bd trg cung da dugc n^fin cuu sau phau thudt. Nghien ciiu cua To chuc xa tri ung thu (RTOG) 0024, dp dung nghien cuu pha II su dung paclitaxel tifip theo la paclitaxel vd cisplatm cho hda xa dong thdi cho bfinh nhdn ung thu ddu cd da phau thuEit cho thdy dgc tinh vd kfit qud dupc cdi thifin so vdi nhdm chung lich sd (nghien ciiu RTOG 9501) nhdn hda xa dong thdi sau phdu thuat dan ddc.
Mac du cac bang chiing dupc cfing bfi, song hda tri tdn bd trg khdng dugc xem la tieu chudn difiu tri trong nhieu vien, nhieu td chuc. Cd mdt sd ly do cho vific nay. Thu nhdt, nguoi ta cho rang hda tri tdn bfi trg lam chfun trfi hda xa ddng thdi vdn dugc coi la difiu tri nhdt dinh trong ung thu ha hgng thanh quan giai doan mugn. Thii hai, miic dp ddc tinh phat sinh tu hda trl Ueu tan bd trg cd thfi ngdn can vific cung cap dii lieu hda va xa tri trong hda xa tri dfing thdi tudn tv sau dd. Thur ba, mpt sd thii nghifim ldm sang vdi hda tri Ueu tdn bd trp da cung cdp hda tri dfing thdi va nfiu da lam nhu the thi lira chgn dd chua ban la tdi uu [l] . Cac nghien ciiu ngdu nhifin tifip theo vfi hda tri lieu tdn bo trg, tifip theo la hda xa ddng thdi so vfii hda xa ddng thdi mdt minh dang dugc tifin hdnh va dieu nay se giiip lam rd vai trd hda tri lifiu tdn bd trg cho benh ung thu h^ hpng thanh qudn.
4. THU6C DIEU TRI NHAM TRUNG DICH
Trong ung thu bifiu md ha hgng thanh quan d ngudi, cac nhd khoa hpc nhdn thay cd tdng bifiu Id EGFR lifin quan vdi muc do dc tinh cua khfii u vd tifin lugng xdu. Mfii lien quan nay rd hon khi EGFR bj boat hod do mpt so dgt bien gen. Vai trd tien lugng cua EGFR d cdc Ioai ung thu bifiu mfi khac nhau ciing nhu dg bdo hifiu qud cua cdc
thudc tdc ddng vdo EGFR lifin quan chat che vdi tinh trang dot bien cua gen. Cho dii ngudi ta chua hieu hfit co chfi smh ly bfinh ciia su hoc lp EGFR vdi tifin lugng lam sang nhung cac nha nghifin ciiu da tim each lie che hoat tiidi cua tyrosine kinase hoac bang khang the don ddng hoac bang cdc thudc lie chfi tyrosine kinase phdn tu nhd.
Thu thfi yfiu tfi tang truong bifiu bi (EGFR) bifiu lfi qua miic Id kfit qua cho thdy bat lgi trong ung thu ha hgng thanh quan. Bonner bdo cao mdt thu nghifim ngdu nhifin cua cetuximab, mpt khang the don ddng chdng lai EGFR, kfit hgp voi xa tri so vdi xa tri mdt minh [14]. Cdc nghifin ciiu cho thdy cai thien dang kfi sfing thfim khfing bfinh, ty lfi kiem soat tai chd/tai vung va sdng thfim toan bp d nhdm thu nghiem.
Dpc tinh trong ca hai nhdm Id tuong tu nhau, ngoai trir ty lfi cao hon cua phdt ban dudi da vd phan ting khi truyen d nhdm cd cetuximab. Tuy nhifin, su dung cetuximab dfing thdi trong thyc tfi cho thdy dfic tinh tdi nifim mac va da cao hon so voi cac kfit qud cua nghien cuu Bonner [15]
Lapatinib, mdt chdt lie chfi phdn tu nhd ciia tyrosine kinase, lien quan vdi EGFR vd EGFR d ngudi loai 2 (HER2) da cho thdy boat ddng trong SCCHN va dang tifin hanh thir nghiem pha III ket hpp voi hda xa ddng thdi. Cdc tac dung chdng khfii u cua cdc chat lie chfi EGFR la do hieu luc tren con duotig dan truyen tin hieu, dan den iic chfi su phdt trien cua tfi bao. Nd da dugc mac nhifin cdng nhdn la cac thudc mdi cfing cd dnh hudng gian tifip dfin uc chfi DNA sua chira, trong dd cd thfi gidi thich hifiu qua cua chiing trong khi ket hgp voi xa tri. Tuy nhien, cdc chdt uc chfi EGFR ciing cd thfi lie chfi sua chua ADN trong cdc mfi binh thudng, gdy tang ddc tinh cap tinh vd phdng xa gdy ra ung thu.
Tap chi Tai Mui Hgng Viet Nam - Volume (59-20). N°2- April, 2014
Ket hgp hda tri vdi cdc thudc uc chfi tyrosine kinase cd y nghia khoa hgc la ca hai deu cd tdc dung tdi ung thu ha hgng thanh qudn va cd co che hoat ddi^ khac nhau. Bang chiing vfi nguyen tdc da dugc cfing nhan trong mdt nghifin curu pha III cua lua chgn hang dau cisplatin vd cetuximab, cho thdy cai thien sdng them todn bg trong ung thu ha hgng thanh quan cd di can xa.
Wirth nghifin ciiu tinh kha thi cua ket hgp paiutumumab, carboplatin va hai lifiu paclitaxel vdi xa tri bang IMRT la difiu tri chinh d bfinh nhan ung thu dau cd glai doan mugn. Ty lfi viem nifim mac vd chiing khd nufit do 3 trd Ifin ldn hon 94%. Ngodi ra 34% bfinh nhan phdi nghi difiu tri do dfic tinh [16], Kies kfit hgp paclitaxel, carboplatin va cetuximab dfi difiu tri tan bfi trg, tifip theo hda xa ddng thdi dua tren cisplatin trong mot thu nghiem pha II.
Phdc dd nay thay la chap nhdn dupc vdi ty le dap ling dugc so sanh vdi cac nhdm chiing lich sii [15]. Trong mfit nghifin ciiu tuong tu pha I, Harrington thdy cetuximab cpng TPF cho dieu tri tan bd trp la kha an toan va cd ty lfi ddp iing 100% d 28 bfinh nhan [17].
5. KET LUAN
Ngay cang cd nhifiu bang chiing lam sang chiing minh lgi ich cua hda tri lieu tan bfi^trp, hoa xa dong thdi va bd trg (hau phdu). Mac dii vdi chi phi cao va ddc tinh vfi he tao huyet. Cac ky thudt xa tri mdi hon (nhu xa tri gia toe difiu bifin lifiu) cd khd nang lam giam ddc tinh bdng cdch giam lifiu buc xa tdi cdc md binh thuong. Cac tdc nhdn mdi nham tning dich ngdy cang cd tifim nang dfi gia tang hifiu qua difiu tri bdng each cdi thifin dap ung va gidm ddc tinh.
Chinh vi vay, dieu tri hoa tri ngay cang dugc quan tdm nhu Id mdt phdn cua bao tdn
CO quan cung nhu tang chat lugng cudc sdi^ cho ngudi benh.
TAI LIEU THAM KHAO
1. Bhide SA, Nutting CM. Advances in chemotherapy for head and neck cancer. Oral Oncol. 2010 Jun;46(6):436-8.
2. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma; three meta-analyses of updated individual data. MACH-NC Collaborative Group.
Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000 Marl8;355(9208):949-55.
3. Ngd Thanh Tung. Nghifin ciiu dac difim ldm sang, can lam sdng va kfit qud hoa xa gia tdc ddng thdi ung thu ha hpng thanh quan giai doan III, IV khong mo dupc tai bfinh vifin K. Luan van thac si Yhpc. 2011.
4. Agarwala SS, Cano B, Heron DE, Johnson J, Myers E, Sandulache V, et al. Long-term outcomes with concurrent carboplatin, paclitaxel and radiation therapy for locally advanced, inoperable head and neck cancer. Ann Oncol. 2007 Jul;18(7):1224-9.
5. Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, et al.
Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced stage oropharynx carcinoma. Head & neck.
1999Jul;91:2081-6
6. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al.
Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J
66
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Med. 2003 Nov 27;349(22):2091-8.
7. Bemier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005 Oct;27(10):843-50.
8. Cohen EE, Lmgen MW, Vokes EE.
The expanding role of systemic therapy in head and neck cancer. J CUn Oncol.
2004 May l;22(9):1743-52.
9. Gibson MK, Forastiere AA.
Reassessment of the role of induction chemotherapy for head and neck cancer. Lancet Oncol. 2006 Jul;7(7):565-74.
10. Hitt R, Paz-Ares L, Brandariz A, Castellano D, Pena C, Millan JM, et al.
Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial. Arm Oncol. 2002 Oct;13(10):1665-
11. Schoffski P, Catimel G, Planting AS, Droz JP, Verweij J, Schrijvers D, et al.
Docetaxel and cisplatin: an active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Results of a phase II study of the EORTC Early Clinical Studies Group. Ann Oncol. 1999 Jan;lO(l):l 19-22.
12. Vennorken, J MR, Vega V, et al.
Cetuxhnab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum based
therapy—^results of a randomized phase III (Extreme) study. J CUn Oncol.
2007 Nov 27;25(6091
13. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med.
2007 Oct 25;357(17):1705-15.
14. Bonner JA, Harari PM, Giralt J, et al.
(2010), "Radiotherapy plus cetuxhnab for locoregionaUy advanced head and neck cancer: 5-year survival data fix>m a phase 3 randomised trial, and relation between cetuximab-induced rash and survival".
Lancet Oncol, 11 (1), pp. 21-28.
15. Kies MS, Holsinger FC, Lee JJ, William WN, Jr., Glisson BS, Lin HY, et al. Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: results from a phase 11 prospective trial. J Clin Oncol. 2010 Jan 1;28(1):8-14. 0 Jan;ll(l):2-3.
16. Wirth LJ, Allen AM, Posner MR, Haddad Rl, Li Y, et al. Phase I dose- finding study of paclitaxel with panitumumab, carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck. Ann Oncol. 2010 Feb;21(2):342- 7.
17. Harrington KJ. Rash conclusions from a phase 3 study of cetuximab? Lancet Oncol. 2011
18. Yang ES, Murphy BM, Chung CH, Netterville JL, Burkey BB, Gilbert J, et al. Evolution of clinical trials in head and neck cancer. Crit Rev Oncol Hematol. 2009 Jul;71(l):29-42.
