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Scsiacr: Assistance with NeutronfX-ray Experiment I want t o thank you and a11 the member. of your ataff. especially A 1 Brown, . Will Talbcrt and Al Evana, f o r your help with our biology experiment ycatrrday. We rully appreciated your active support and in tert at, which contributed so much t o one of the nomt successful up rr in r nts(at leaat la Ita techoical ue cut ion - - velll have to wait some time for re rul ta) ve've done yet atWL. I explained t o you, thia experiment is very Important i0 testin8 a hypotheria wm've d.ve1op.d aa a result of our pion radiobiology and clinical obarrvatious. Attached i a 8 copy of the paper dcacribing thl8 hypothesis which was submitted although I would appreciate it If you vouad not reproduce it until we know whether it has been 8ccepted f o r publication. to a Friday mornlw conference ioae t h e when It I s mutually agreeable for our tchedulc8 *topresent this material t o your group. I waild be glad t o hpve you ahate t h l a copy with your group, 's\ A. we discussed, f uould bq glad t o come
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applications of negative pi mesons (pions) in cancer therapy. Phase 1-11 clinical trials of pion radiotherapy 8 n noi'- underway a t the Los Alarms Scientific Laboratory, Lo. Alams, New Hexico, in cooperation with the University of New Nexlco Cancer Research and Treatment Center. Compared t o 100 kVp x-rays, 8 therapeutic gain of 37% h8s been suggested for pions based on dat8 compating time to tumor regrowth a t 300 days with equivalent acute akin injury produced by graded doses of pions and x-rays in a pat fen t with 16superficial breast tumor SubsequentXy, anecdotal observations on patients treated with large tumors of the head and neck, lung, and pelvis, whero nom1tissue reactions and rapidity of regression could be assessed, suggest thata therapeutic gain txistr for pions in sites hypothesized that this therapeutic pin is related to the simultaneous occurs i n pion radiotherapy, and is separate from the advantages which also accrue by the capability to localize the pion Brogg peak and star forrratioa vith in the tumor volume. It is, therefore, hypothesized that this therapeutic *These investigations were supported i n port by U.S. Public Health Service Grants KO. C.4-16127 and CA-14052 from the Katlonol Cancer Institute, Division of Research Resources and Centers, and by .the U.S. Department of Energy. University of Ncw Mcxico, AXbuqucrque 87131, and the Los A~ZMXIOSS cie nti fic Laboratory, Los Alamos, New I.Icxico 87545. From the Cancar Research and Treatment Center and the Deportment Of b di OlOgy, Submitted t o Nat tire 1 0 1 5 2 5 1 HSPT
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g a i n might also be obtained by'thc near slmultanaous application of hfghx-rays* respectively), although the added benefit of doso locolizatioz vould not be achieved. The effect of piolu on biological systems was predicted t o be intcrnediatc between that of pure neutrona and pure x-rays. On single cell ssstcar, i t war expacted that pions vould result in some reduction of the shoulder of t h e cell aur viva l curve and D , and some increase in the elope of the exponential portion studies at the Loo Alomoo Heson Physics Facility WP) hova shown. thech8roc teri stic has been a uniform reduction of theD by a ralatiXvely constant number of rad s irrespective of the original v ld th of the x-ray D . a number of ex per hen to using single doses in the range from 40 to.800 raCs, little change i n the slope of the exponential portion of the cwe occurred. The mechanisms uuderlyiag thia phenomenon a r e still under investigation. In actual experience, this is not what the bio log kol In experiments ulth multicellular tumor spheroids (MTS), in vhic5 growth delay after graded doses of radiation io macured, a number of factors contribute to8region of no detectable response (Dnr). to the D in single cell survival curves. ( 5 or 10) than for single fractions. o8me number of rads), as opposed to a percentage reduction, of t h e Dnr occurred when multiple fractions, up to 10, uerc given.8 With fractionation, the slope of tho x-ray 8nd pion CUNCS became less acute, but rcmalned parallel. difference in width of the Dnr for pions versus x-rays increased narkedly for This region is analogous It is larger for multiple fractions A quantum reduction (approximately the
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multiple fractions am compared to single fractions. t h e doscs ranged from 40 t o 160 peak pion rads per day and fron 100 t o 240 x-rpy rads per day. four to f i v e tlme8, although t h e .mount of reduction vas essentially chr 8-8 in An examination of the reduction i n tho Dnr for single and aul tip le two HTS systcm3, one with a large Dnr and one v i t h a modest Dnr. Incidentally, Yuhas has shown that with single doses bctveen 100 and 600 rads in the NIS c e l l line K-A31, which has a zero Dnt f o r x-rays, the Dnr f o r pions was also zero and therefore superimposed on that for x-rays. 9 A. expected, there was an increase in the relative biological effect is (RBE) vith 10 fractions 8s compared t o the RBE for a ingle fractions. occurred i n MIS of cell line HCa-11, vitha modest Dnr and NTS of cell Line 1 lung carcinoma, with a larger Dnr. inru both lines,a greater percentage increase in the RBE occurred with fractionation i n the cell line with the smaller shoulder. Due t o the same quantum change i n the D The amount of high-LET radiation In the peak region is relatively loa (see below). Howewer, because of the magnitude of the biological e f f e c t observed, it was theorized that small amounts of higli-LET radiation decreased the cells' tolerance to the injury created by simultaneously adnlnlsterod at periodic in t cr vals ranging from four hours before through four hours after a standard peak pion dose.' occurred when x-rays were given from 45 minutes before to45 nir.utcr after To prove this, Yuhas gave x-radiation to cell cultures the pion treatment, wiCh a peak e f € ect uheh the two treatments xcrc given 08 close t o siu~ultoneouslya s could be technically accomplishcd. Subsequently, he found that 50, 75 and 100 rads of pions were effect iv c in potenti a ting
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-X-rays, b u t 25 rads of pions were inadequate. Further, the addition of pion r8ds beyozld 100 gave no increase in the potenti a ting effect. Ibte t@Cently, 8 riPtlor the survival curve using heavy ions followed by graded doses of x-rays. uaallrr shoulder Y8s found without change i n the slope of the single cell (V79 Chinese hamster cell) survival curve. It is hypothesized th8t this relatively. constant m u n t of reductiorr 7 of t h e D qnd Dnrwithout change i n slope could be the b8sis of P therapeutic gain, which may be developing f o r and could possibly prevent untoward In the peak region of the pion beam (the stopping reglon, which can be 8h8ped t o the tumor-bearing volume), the proportion of low, medium 8nd high LEI comprising the total dose varies the peak region is spread in t h e z dinenoion, Specifically,the high-LET fraction decreases as thez dinension increases. This vfl l occur irrespective of the manner In which the pion .topping region io applied tothe treatment volume, that is, whether by 8 st8tic beam or by multiple small cylinders or spheres of peak pions. Inthe static peak mode, the entire volume of tissue to be treated is simultancously covered with stopping pions, by modulating thc peak so t h a t it spreads over t h e tumor volume. Norc than one portal of entry is commonly used but not always pions entering tho patient by two o r more portals will scan the tumor In dynamic scanning, a narrow cylinder or smll sphere of peak--
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volume i n the t dineasion, 88 the patient is translated perpendicular t o the 0x1s of the cylindrical peak, until the tumor volume I s covered. The tmor vo~umecan also be filled vith peak pions delivered by the d ti - of Sucleor Research- A t this writing, the method OF pmk pion delivery at LALLPI has not yet been converted tothe dynanic scanning de. percentage of high-LR component (>80 KeV/pa) i n the static b e a r s now being rued varies with the length of the t dimension, but i t is surprisingly low, something on the order of 5 or 10 t o 20%, but probably closer t o t h e lower figures. ' Clinical studies with pions 8t LA!!!!F began with Irradiation of , superficial metastatic skin nodules and the surrounding and underlying normal tissue. Sixty-five tumor nodules i n seven patients were assigned randomly t o trcatnent vith graded doses of pions or 100 kVp x-rays. Results indicated that pions were 1.42 thee more effective than x-rays of the skin,' One of thcae p;tients, uho had 1 6 tumor nodules (primary breast), could be followed for 346 days before additional trcatnent was required. pointed out above, analysis of data on time to regrowth oE her nodules shoved that normalized closes of pionrr vere 37% more effective than x-rays i n repressing A regrowth a t 300 days, for the same amount of acute skin Injury. This was the first indicator of therapeutic gain for pions, l.e., greater turzor effect for pions far the same amount of acute skin injury. Subsequently, pions have been applied to larger and deeper tumors of various anatomic sftes. Analysis of data for 52 evaluable tumor8 in 20 patients trcoted
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with pions only ( p r i o r to Decmber 31, 1977) and follovcd for 5 t o 22 month8 shoucd that 42 tumors. (812) completely regressed; 3 tumors (6%)partially rugressed; and 7 tumors (13%) d i d not respond. Five of the sc vm which did not have shown no grouth for 10 months. Additive conventional radiation was given to eight evaluable tumors in seven patients. responded and five partially responded. complete and one w i t h partial regression) revealed no tumor microscopically. Reactions In nom1tissues have been mild, with some patients exhibiting Of these, three t mors co zp let t ly The resected specirncns i n two (one Vith esoeatfally no normal tissue reaction, whlle tumor response has in many cues dh rth ca, and no patient treated to date has experienced radiation sickness. For example, no patient receiving pelvic irradiation has exhibited Further, no fibrosis has been observed Inpatients treated from 7to 24 mntb It should be noted that the pion doses have been applied witha wide margin of 8afr ty in dose until effects could be observed that would indicate higher doses could be tolerated, in an effort to determine tolerance for various normal tissues prior to initiating Phase III clinical trials. Nany patients vith large (T4+) lesions have exhibited complete tumor regression, even a t what appear to be subtolerance dose levels for normal tissues,often before the end of their course of pion therapy. These responses are significantly more rapid than could be expected with conventional therapy. Again, those anecdotal observattons indicate a trend touard therapeutic gain for pions in sites othct
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figpotlrasis f o r Mcclmnism of Pion Therapeutic Gain As notcd above: 1. Pions have sihown 3yel at iv eQ constaut reduction of the uitouldrr of the survival curve for ring lt cell cultures and relatively constant reduction in the no response regton for multicellular tumor spheroids OnS) with little change In sensitivity (or rrlopc), i n both single dose and fraction a ted rxparf2. The pion beams used therapeutically a t LAHPF are characterized by 8 small amount of high-Lfi radiation (approximately 5 or 1 0 to 202). 3. A trend toward therapeutic grin for pions has been demonstrated in p8t it nts treated at WWF, with marked, rapid tumor regression for relatively mild acute normal tissue injury and no untoyard effects observed over 7to 24 Based on these observations, a hypothesis has been developed which baser t h e therapeutic gaia observed f o r pions on the quantum reduction obrrrocd in the shoulder of th t survival curve for single cells, and In the no response region for HTS given Purltifraction pion irradiation. contribute to the restitution of the integrity of normal replicating tissues under fraction a ted Irradiation, from clinical observation the net effect is consistent with the premtse of an increased repair/recovery capacity for normal Although many factors t i s s u e s as compared with the majority of tunors which arise within thcse normal Fig, 1loo representation of o hypothetical reason behind the therapeutic gain. The model assumes a larger shoulder for noma1 repli(00132793.007
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tissue shoulders t o 300 and 100, respectively, or a ratio of 3.0. in this model, pion radiation as compared t o x-rays in crt as es the diff cr rat i.1 tolerance to sub lethal injury, fn favor of normal tissue, by 3 to 2, €or therapeutic gain of 50%. TIIO normal tissue ohoulder t o tumor tissue shoulder ratir, is In this nodel. piom reduce the shoulder of each cell line the sa=% Pion treatment chonges the w i d t h of tlia noraal and tu=or Recammendations for Clinical 8nd Economic Exploitation of Observations ufth tho Pion Beam While pions have the added advantage of dose localization, i.e., confinement of the high-LET component t o t h e pion stopping region, the observed differential effect of pions on normal and tumor tissue within J& stopping region is an added benefit-one which may outveigh t h a t of dose localization. To mimic this advantage, wing other types of radi.tion, it i r proposed that daily fractiono of neutrons and lorLET radiation be combined within 10 minute. of one mother,ifnot delivered simultaneously. Thio ehould create a biological a it u ation similar to that of pion treat neat, which is composed of a small fraction of high-LET radiation and P large fraction of medim- and los?-L€T radiation, delivered simultaneously. It is belicved tht approximately 10% of the daily dose need be high-LET radiation. Perhaps -ximally 15 rads of neutron radiation need be delivered of a total of 100 rads daily dose. (With regard t o dose localization, some improvement could occur by cross - firing neutrons and x-rays on different axes.) The required neutron generator need not be of high intensity. Evcn with an output of I - 5 rads a minute, the neutron treatment could bc
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dclfvercd in thrcc t o four minutes. The patient could thon be transferred im-edfately to an …
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