Treatment of Cancer with Helium and Heavy Ions

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Lawrmco Berkrly Laboraloly Abstract ; This research project will study the therapeutic app li c6tions of BEVa4C-produced heavy ions such 6 s neon in the tree t ment of human cfincers. While pre therapeutic r sdio b lo logical peremeters for heavy ions are being Bregg-peak radiotherapy using helium ions ev s ile ble from the 18b-inch synch re cyclotron. The radio ~ io logic e lparameters of this beam are well established. The ex per isn ce gzined in treat oen tpl inning,setup 2nd inplementstion with the helium ion beam will be invaluable in carry in6 on ir rh di atl on with the heavy ion beerr. Pilot studies leading esso m is p2s s iSle to controlled stu3ies will be performed. Controlled studies are plsnned with both helium ions (to study prirnarily effects of irp r - wed dose localization) and heavy ions (to eva lost e bot'r. the effects of irq roved dose localization 6nd the potential r sdio bio logic etv s nt ~ g eof g rest ly love re & O S (cxygen enhancenent rerio)). The change from ortho volt to megavolt rb dio therapy techniques provided the ability to deliver an in cress ed radiation dose t o deeply eztred8ed structures together with d hi notion of dose to uzi c vol ve dnc melt is she s. Tris ic proved dose dist rib uzi on le6to an increase in local c orz ro lr ces tr18 e te crease in normal tissue reactions and nor jid it yin an w ber of hunsn t'amor sites. h'evertheless, local and region el failures still account for e sizable proportion of instance siri w n ich red io there py fails to control the tumor. advantages ix is tin heavy ionr6dio there W which may improve the tmor control : 6cleer inprovcoent in the ability to deliver e higher dose t o both ;mor and tre a x w nt vol me with a decreasing dose t o normal tiss ~ e s lying near or sur r our ding the treatment volume. A n inproved charice o f tumor control secoadary t o the physic el properties of heavy ions, particularly the decrease in oxygen enhancement ratio (Om)shownl~fObe present with increasing linear energy transfer (LET). The use of helium ion there py for the first phase of this study will hsve its potential advant&ge primarily in the e bil it y to better deliver 2 more loc z liz ed dose to the treatment volume and minimize the dose t o i n terms of decreasing OER compsred with conventional r6dio t ber & ~ i.Toten tiel Iadvantages therefore,are found in cl lr.i ral situ et ions s here the akil it y,o surrounding normal structures sith cczvectiorial low LET red;otherapy. Because of the steep dcse-response rel zion ships for both tumor end nor321 tissues, smell increases in the t ' mort.cci. such ec this techrAque per nits, consider e ble velue i n developing :I eb;=i=n;. techr-iques with he eq ions 2s well es providing e control group for conperison of heavy ion therapy, where hoth the a dvm ~ ege sof beztez dcse 1oceli:at;on and significantly heavy ion zrierepy include : 1) tun or s tiet heve necro tic portions end ere :L=,G~S tinst carr DE precisely ls cali zed

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2d:tcer.t io rEd ics ens it lu e structures which cannot be a\,oided es sil y i;$ifig 6) t > m a + svhich do not nets sts size rapidly ; and 7) very small tl;oors. O n locally controlled in greater thir 75% oftie casts oy sure or y, conyerjtional adi ation,or .%-ailable c3emotherapy with acceptable nor bidi ty ; 2) t uz or s controlled clinical%rial of helium ion therhpy end gaining experience applicable to heavy ion therapy when it becones a veil able. sf the ilzerine cervix, prostate, bladder, ovaq, and/or rectum; of tie brain ; no mcl tir sues may be important such es certain prostate, bladder, or rect zl and 3) t,.unors which cirnnot be properly localized. Accordingly, our initial efforts will be directed to uz r8s conduct ii ga 1) pars - aortic lymph nodes i n such tllmors a s cercii,oma 3) soft tissue sarcomes; 5) pelvic tumors where dose localization and avoidhnce of 4) localized pancreatic tumors and The theoretical advantages o f heavy ion, high LZT radi at ioc s were first recognized by physicists 2nd biophysicists because of the relatively low en era deposition(plateau)until the critical distance has been t reversed rrignt be translated into low entrance and normal tissue dose relative 50 tie critical depth of interest. physic el aose distribution, biOlOgiCa1 parsmeters namely OW, which i s dec reise d for high LET radiations, is hoped to give a prefer en tiel advantage over s ro xtc t mr cells. i ov UT radi bt lons on anoxic cells. ir. theXE(relative biological effectiveness) of the pesk radi st ions relative to the plateau radiations. difference in LET of the radi at i oz s in different SreeE of the depth dose Experimental sna1ys:s of helium and heavy ion beens in clu dir g carbon, At this point,8 many fold increase in the dose deposition occiirs This physical dose distribution of the radiation In addition to the obvious edvantages of the This is in contrast to the protective effect of An hd6it ioc al theoretical Bein lies This is most likely due tothe brgon, oxygen, and neon have been underway at LBL for sone time using first lov intensity beams ofthe Bevatron and more recently the high intensity end heavier beam of the BEVALAC. The BEVAJAC project,financed by ERDA hes as one ofits major aims applications of high LET radio biology for the.purposes of radiology. A great amount of.r a dio biological research has been performed both at the helium ion facility at LBL (thela - inch synchrocyclotron) as well as on heavy particles generated by the Bevatron md the BE VW.Radio bio logic el measurements have been carried out in both the plateau region of ionization e6 well8s the pee region of ioniz,ation utilizing different culture system including hwu, Bi6,ney cells, Chinese hamster wary cells, bone Di iT rW, and mouse testes.A swy of thera & io5io logical data is listed on Table I. oe a will gsc era U y be used in its therapeutically modified "spread-out" form i n w5ich the helium ion, Bragg-ionization curve with its s iz & e peek i s transformed into a flattened depth dose distribution so that cell killing is constant along the last six to tencent i a et ers of range. See figure 1. This is done by inter positioning into the beam pstha moving copper ridge experience over a n*mber of years has been gained with hi&h enera protons and heii ' mions. For the purposes of human there pe u tic ir redi ation,the he li union The first therapeutic human exposure t o hign er.er&v deuterons

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Archlvw and Rrcordr Offh ion ti.eizpy, pa: tic itz rly for 1esior.s of the pituitary. These tre ht a ents Fart 11. Specific him riiio5:"ernpists t o prep're for zi d pert ici pete in9clir.ica1 e vast uel ci5ii cel trial phase. ? val u ate irszsing 6nd density distribution uessiirene~it techniques to aid in t.L?or and t,rc-&tmentv o l ~ z elocalizktiion. !..ssess tech c ical problems of larEe fi eid fzs c tio tz ted he li im io norte wy io next tn ded Bregg peek Lherapy with re spem to shzpe; and c) dosimetry, including essessment and csr rect ion of tissue inhomogeneities. Treat a select group of patients with large field, fra c Ll on a ted Bragg peak the r spy,using a heliiur ion hean? init.ially, proceeding 2s soon as feasible to high ET heavy ion therapy. Design protocols for and initiate a& soon as pos s it,le controlled clinical trials of selected hunan twors conpsring helicm ions to t ne best a veil a hle low mT radiotherepjr tecimiques ai:.?. when Evailable, in a thx ee KEY rEr : d o ~ zati - . n TO higb LET heavy ions. E x - i l ~ jet ep ossi bil it y of ver if i - ing k ez q ion test 3gse8is tri b.Jtion by autoa ct iv a zion. sires for helib:s-i-icevy ion thsrspjr, Dotn pilot phase and Part 111. I4ettods of Procedure The initial ptr-se of this pro2ect will stress en une lysis of those - loc a i izz zion possi?lr vl th he lim ioc - key ion beans. interest with ne1i.m i0r.s will he directed to u erde vel u ation of improved results primarily &;e to Setter localization of the dose, with slso of e s'iig,hclj. :r?rc;ed i ; io logical response. will se nez ste fc-:,k&tion upon uh ich to plan later heat-y ion tnerepy -wilere one does e>.??ct iz?Ioved results fr m the greet er tio logical effect of these phr tic ies on ;?.e tmor as well 8s the comparable sparing of normal tissues due tohe ; ter dose loc el izz tion. tes indicated Cia w2ere an 5.rr.p-oved tunor dose localization has been These > eli union stildies Considerable historical inforntition These co c side ret ions hue been summarized by N. coi > tir,.ij They concluied that u here ti or ~ cse sof

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ip prC r.i at ely 7000 rzds i n seven veeks cen be deli \ ered with present conventional tech ci pu es,local control E iii g it '>e only slightly %!:proved by better dose local i zh tion, although morbidity mtiy be dirdr,isF.ed. Wten hoses of this level cannot b e reeched because of lin it at ions by norltal tissue tolerance hcvever, the improved d is tri bc tion from proton the r spy right ellow tn or ici6el doses of approx in et ely '(000 rs6s t o be delivered with conseqbent increase in local control. therapy fall generally into tile seme C ~ Ess if i cation sas proton therapy because of the slightly higher EBE of 1.2 and probably only minimally inproved Om of approximately 2.3). suggest the fol loGin g sites for possible irrprovement of loz el results: carcinona of the stombch or pancreas, retro per it one zl tissl;e, phre - aortic region, base of b lsd der and prostate.As initial tL mor sites for treatment d th helium ions W e are considering Crsde 111 or IV tistrocytonas, psraaortic lymph nodes, localized phr crest ic,renal,md esopkageal tumors. Car c in s nat a of the stora ch, hlaiidder, soft tiss>.,es end the kad and neck re6ior.s are arong the sites t o be ev zl ue ted a tale ter date. gene i ties must be recognFzed and the appropriate in form z tion in corp of it ed in zo treat nen t planning. regarding such in hom gene i ties my he oj tai ned through careful imaging techr-iques, incl'iding transverse tomography, ultrasonography, and standard raeiograpky. Ce ref ul surgical exploration with precise identification and clipping of the tmor vol u es is an essential part of pre treatment ev slu ation as it IS with low UTi rr a diet ion. Smprovenent in treatment plar3;ing tech ni gue s Gill be forthcoming with the use of computer assisted axial tor?ography which will provide accurate tissue density cross sections for treazment plan n bg.Individually prep wed absorbers (bolus) will compensate for tissue in ho no gene i ties toes sure proper distribution of (Consideration for helium ion Our initial planning will thus be directed to tm or sites where e n In co c side ring tun or sties to be irradiated,tissue density inhomoFor some tumor sites td equate density info nation - t h e helium ior, bean. absorber materials and computer directed energy motiiule2ion to control *e depth of penetration of the extended- Zregg peak cbn b e used. addition, we will be exploring with other IBL r sseL rc5 groups add it i oz el avenlies of inproved localization techniques. Tazse include the fol loving possibilities : 1) heavy ion r dio graph y ; 2) he lit mi on radio&raphy; 3) heavy ion CAT scanning; and 4) auto activation, which involves t ne use of a positron scanner to verify the distribution of dose. helium ion-heavy ion irradiation are those ui th Grade 111 or IV estrocy;omes csing "boost" tLerepy following whole brain radiation to a besic dose level of perhzps 4000 o r k500 rads in five to six weeks. e bil it y to localize the helium beam will provide s iec if i cant sparing of - o mel brain tissue vh ile raising the primsry tumor volune dose t o the ~ 3qui vel en tof 7000 rads in eight weeks. Althouzh one Lght not expect of treat nen ? shocld be less Eaking this site wort2:i of fee siri lit y studies in preparation for he a wi on therapy to brain tumrt \ here a bio logic el advantage may be demonstrated. para - aortic lymph n&es, which are known sites of nic ros cop icc e testes es from ve rio usp rl ~ s r ysizes including car c in or at a of ;:.e uterine cer vl x, For treatment with the BEV+kC heavy ion Seam, Among the pet i ents suitable for initial fez sibi lit y studies with An a:ea of greater interest perheps is t bet of irradiation of the

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ir re a i it ion in the lynph r:o&s SecaLse of s is ni fic in t morbidity from Befined 3 ~ ~ 7 3Eose distribution Cchlcveble vith helium ion be- can be elf ect iv ely Gti liz ed to ir radi k te those noses t o it leest 5000 rhds in five WCC-:..~ vi:h zri expected decrehse ini ~ orL ldi ty. Higher dose nay be fez sib le be cw se of the lower integral dose to the intestine. Dlinnirlg zpprsach would use a direct posterior field,with the appr opr it te cc,zpezsetion for vertebral bone within the treat nen t port ; it might re qc l re dcse of e s7tr.Ele entry portal. be z chi ev sd t'&Too,-'n the use of multiple ports sp prop riE t ely weiEited t o nir.irl ze the Bose ioe dj a cent intestine. Loc sli zed pan crest ic tumors present the EC-me prohlem uith rtEerc! t o 5we l to lerm ce ad,in u id iii on,re cui re plarming to c in l rize rzdibticrn dose to the liver and kidneys. of tux or by Clips would make precise dose loc sli iet ion piss i ble with heli-Ehezvy ions, using ap ? ro pri a tel ? .selected portals t o minimize t ben or x.1 tissue in j urL - .In …