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Machine-read from the scan, so expect some errors. Lines that couldn’t be read are left out.
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Harold H. Agnew, DIR-0, MS 100 DATE: September 9, 1976 As a result of our meeting yesterday, I have made some calculation e and consulted with radiotherapists \ whose judgment I trust, t o determine how I can work within the framework of projected production cycles and beam intensity presented by Dra. Rosen and Hagenaan. with superficial nodules, we aze ready t o proceed to larger tumors. The existence of the pion radiotherapy program is predicated on the need for a batter treatment for large, deep-seated primary tumors not well managed by any current modality. We cannot expect to receive patients with small tumors; those are already curable by other methods (i.e., surgery, conventional radiotherapy, drugs, or a combination of these). With an RBE for skin reaction of 1.4 now ee tab lie h td by our tests 2. While relatively large doses of conventional radiation can be safely given t o small volumes, doses larger than 150 t o 180 rads of conventional radiation per day cannot be given to large volumes without impairing the recovery ability of the normal tissues, which significantly increases the potential for patient injury.bide from the ethical and legal considerations, the occurrence of injuries in our project,parti - cula rly at this early stage, could jeopardize the future not only of our program, but, indeed of all high-LET radi at fon projects in the country. 3. Given an RBE for skin (an average tissue in term of tolerance to high-LET radiation, as determined by neutron data) of 1.4, the daily dose of pions which can be given safely with curative intent should be inthe range of 107 t o 129 rads per day. fractionation schedule conforming t o the production schedule prcnented by Dr. Hagermen) is 5600 rads of x-rays, total dose. begin treatment atthe 60% level, we ehould be able to treat pion patients safely under a 22 fraction schedule (5600 + 1.4 i 22 x .60 109 pion rads p e r day). A curative dose level for 22 fractions in 2 5 days (a maximum Since we will 5 . We will treat only a few patients at the 60% level before escalating t o theJOX level (my national advisory committee recommended o ix patients a t each dose level before escalation, based on observation of tolerance, for each anatomic site or structure). be atthe upper limits of safety (127 pion rads/day). We will not be able However, w e could still treat a relatively large number of patients this year if a sufficient variety of tumors were made available to us, except for two factors : (a) limited depth of penetration into the patient with the present beam When we escalate to 70%. we will t o go higher on a three-week schedule.
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tuning configuration, and (b) limited Intensity of the proton beam. could expect mmximum penetration into the body of a total of 15 cm, including a maximum peak area of 8 an. tumors lying in their entirety less than 6 inchen from the body surface. (You will remember Dr. Wnapp was exercised at the meeting when he thought that I stated that this was a permanent site and depth limitation.) It had been my underatanding for t!e past four years that penetration of up t o 28 cm could be achieved with the range shifter, though I had agreed t o accept 25 cm. It may be possible to achieve that mudmum within three to four months, I was told, but i t is not possible now. This means that I will not be able t o accept many pelvic tumors, so that rectal and vaginal tolerance could be determined, which I wanted t o begin to study at the end of October. t o head and neck tumors, for which there is considerable competition from other types of clinical investigation, and, therefore, which will be difficult to access into our study. Thus the potential number of anatomic sites which can be treated in t h e next nine months may be severely curtailed, and therefore the number of patients. I vu made aware yesterday for the first ti- that in October w e This limits us to treating Now, we will probably be limited I was late for the meeting in your office yesterday because I was asked by our physicists to look at this situation, compounded by the patient positioning and body penetration constraints imposed by the current energy and the range shifter. Access t o the treatment room was available only as one physics experiment was ending and another beginning between 7 and 8 a.m. I apologize for being late; I do not apologize for using that hour t o look at this important problem. I was already six hours into my work day when I arrived at your office, having started at 2 a.m. (which, as you know, I have had t o do far too often since coming t o New Mexico). I know, for my part,it is not conducive t o amicable meetings. However, it was immediately apparent tome that a meeting had already taken place. 7. In the larger static beam now being prepared (8 x 10 x 7 cm), Dr. Kaapp estimates w e can obtain a dose rate of 2.75 rads per minute, with 100 microamps of beam current. n o t much more, and we cannot count on doing so. this lov intensity in biologically effective at that rate (I think it is, but many radiotherapists and biologists including some members of the LASL ataff disagree), a daily fraction of 109 rad s will require that a patient be immobilized under the beam for 36 minutes; a daily fraction of 127 rade will require 42 minutes. If we are to do all the necessary physics and biology needed for our project,we must limit patient treatment t o an 8-hour shift with each cycle. maximum of six to eight patients per cycle, allowing for set-up time and intermittent down-time. Given the potential of eight cycles for patient treatment between October 31 and t h e end of August, w e could treat a maximum of about 50 t o 60 patients with this mediumsize field, but only tothe 70% level (which would not be t o our advantage orto that of potential patients,if sufficient information can be gained about effects at those dose levels with considerably fewer subjects). M y experimental designs have so far been unbelievably successful in giving us human biological data in a very brief time. This may be increased t o 3, but probably Assuming thata beam of Thus, we will be able to treat a
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Further, the8x 10 x 7 cm volume is still relatively types of pat imt8 we can expect t o be able to accem. Dr. ue could obtain an8cupt8ble dooe rate in a larger volrpu a scanning beam and 8 couch transport syrtem. I had hoped small for the when we go t o will take a h months), and obtaining a movable couch system. Since Dr. Knapp ertlmater that at 1 milllamp we will have 30 rads per minute ina liter, 100 microamps should produce 3 rads in a liter. Thir meam w e could treat a larger volupre in about the 8- time required for the mediumsized volume, butif we are still conatrained toa three-veek operating cycle,we Will have gained nothing. 8. In the spring,u a result of my conversation with Dr. Roren, Dr. Bagexman understood my need fora seven week treatment schedule t o begin around the end of this calendar year (see attached documentation). Hsd he talked tome about the coming year before making the decision w e heard yesterday, I would have presented the above calculations to determine what we would require. Dt. Booen and he knew from pravious discussions that seven week were needed for curative treatment, 8nd furthermore, th otto acceas patients from around the country would require a nine t o t e n week production cycle. four day) d a m periods. week development periods. The reason a t least nine and preferably ten ueeks are needed is t o give our referring doctors an opportunity t o refer us cases. If not, everyone would have t o arrive a t the start of each seven week cycle, and patients vho would be available on Day 1or beyond could n o t be accepted. This could be broken by three day (questionably m, they kneu I could tolerate up to three In other words, our accession rate would 9. Concerning the question of split - course therapy, I must state that split - course therapy vlth conventional radiation is still experimental. The prospect of combining one rxperlmental treatment (pions) with another (split-course) and then attempting to evaluate the results vould be a potentially dangerous undertaking, medically, sci cnt if icd ly, and politically, in my opinion. Today, I consulted the statistical analyst f o r the Radiation Therapy Oncology Croup, vhich has had a protocol under way for some years to study split - course treatment. He told me (as I had observed with thir type of treatment a t Yale) that the incidence of adverse effect o in normal tissue (thus the potential for injury) is probably higher with split-course. The head of t h e RTOC (Dr. Simon Kramer, who will be heading our clinical pion radiotherapy grant site visit team) ha8 stopped using split - course because he feels he know it i o dangerous. I am certain he would not be amenable toa discussion of split - course at our site visit.Similarly,Dr. Joseph Castro, trained a t the M.D. Anderson Hospital, one of the leading young radiotherapists inthe nation, a mePIber of my national advisory committee, and the medical leader of the Berkeley heavy ion project, has stopped using split - course for the same reason. Dr. Samuel Hellman, Chairman of Radiotherapy at Hsrvard and a mOmber of my advisory committee, told me he felt that i f ve combined pion0 with split - course fractionation and obtained adverse results, w e would not be able to determlae which was responsible. Since I feel we must minimize the possibility of adverse results while progressing t o reasonable dose levels, I could not in good conscience a l l o v more than 3 t o 4 days between courses of treatment as
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10. There iaa similar argument again rt cmb in in gr raya vith pio mat the outlet,u we then could not determine the full effect due t o pion# alone on normal struct umi i, which ia the purpose of thene early tests. Further, there i. already such a large lor LET coq one nt in the pion beam that c dining thi8 with other lar LET radiation at the early low doaa levale (60-70%) night produce little or no appreci8ble effect. Thw, we could treat a number of patients pad have no data for our effort. We would not know ifa negative anaver was due t o pion8 OT bee a we one had not we dpi ow alone or continuowly. substitute x-rays vhen our fractionation is interrupted by breaks i n the beam operation, because it is most important t o preserve fractionation. Harever, t o do this ab a matter of experimental design would be open t o Ue miat occarionally 11. Given these prospects for the coming pear, I am frankly worried that the NCI will discontinue support for clinical trials with the potential of treating eo few patients,particularly with the preoent keen competition for funds among the varioua high-= projects around t h e country (many of which are not presently funded becauoe we bold such a large proportion of available radiotherapy research funds). Our pion project hae been receiving $1.5 t o $ 2 million per year for the last four years (almost a million to LASL this year, plu the ERDA joint interest funding based on continued NCI support), for very little return in clinical opportunity. I mn willing to work within the constraints impored by Dr. Rosen and Dr. Hagennan, even tothe point of severely curtailing patient treatment; my concern is that the NCI may not be, but LASL must convince them that the situation will change rapidly as of October 1977. However, since our first proposal i n 1972 (four years ago), the schedule for achieving 1 milliamp has slipped five years and 500 microamps. Each year I have been in the position of promising things to the NCI, based on my best information a t the time, only t o be unable to fulfill t5ose promises. Be assured this site team will be mare of these facts, as they are given summaries of previous proposals and progress reports by the NCI for background revfew, and our project io under continuous discussion around the country and abroad by jealoue cowetitorrr. 12. LAMPF will continue t o function with or without NCI oupport t o the pion biomedical program though you as well a s Dr. Roren use i t ao your showpiece particularly with the Congress. However, the existence of the W M Cancer Reoearch and Treatment Center, from the NCI p o i n t of view, is presently predicated on the availability of pions a t Los Alms. M y effort o to effect the clinical pion program have interfered with broadening and atrengthening our Center on other fronts, which Dr. Hagerman's decision has now made me realize I must do as rapidly as possible. Furthermore, I believe the people of this region deserve the same kind of cancer care as those living in other, more heavily populated areas, and we have many other ideas about how t o cure cancer (in addition to and far more cost - effective than the use of pions), which should be put t o test and vhich t h e pion project has made me set aside. This is why we are seeking Comprehensive Cancer Center statue and why w e are separating our care support request from our pion clinical project request. Currently, the viability of the CRTC is severely affected by the operation of the LAMPF accelerator, by its impact on the potential for continuation o r loss of our funding from the NCI. We hope this vi11 not be the case within a very short time, but for the present that is the reality which I and my staff face. All that we have been able t o muoter for the past five Years is a t stake in this series of site rev iw s. COPiED FP!3*756.004-
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governed by phy8iCi8tm' considerations cawed 8uch a furor. i n response toDr.E age mn ' s c-nt that an important reaaon for experiments more efficiently. about the need for raven and tight-week cycles, (and, therefore, ten veeks t o accers patients)to diz e potential for normal t i ~ rue recovery in patients.Iwu very surprised th8tat …