Mice and Men
By the time the danger from neutron rays was appreciated, high-energy x rays no longer held promise for cancer therapy. The result obtained by Lauritsen and Packard of Columbia's Institute of Cancer Research in 1931—that 550 kV rays had no more deleterious effect on Drosophila eggs or the common mouse tumor "sarcoma 180" than an equal quantity of 50 kV rays—had been substantiated and extended. Lawrence had conceded to Wood that the 1 MV Sloan plants probably would have no greater curative properties than standard x-ray apparatus, and experience at the University's Medical School fully confirmed the concession.[98] Hence the possible medical value of neutron therapy held unusual interest for Lawrence both for itself and as a replacement for a played-out technology. A principal objective of the very first experiments with neutron irradiation was to compare its biological effects with those of x rays.
John Lawrence and his technical advisor, Ernest Lawrence, who in July 1935 became "consulting physicist" to the Medical School, exposed $120 worth of rats near the beryllium target of the 27-inch cyclotron and at the Sloan machine in San Francisco. The neutrons appeared to be about ten times as effective as x rays per roentgen in altering the makeup of rodent blood, or five times as effective per unit of ionization since (they estimated) a roentgen of neutrons made twice the ionization in rat tissue that a roentgen of x rays did. Since the standard tolerable limit of x rays was 0.1 r/day, they recommended prudently that the maximum for n rays be 0.01 r/day.[99] While the Lawrences zapped rats, Aebersold and Raymond E. Zirkle, a medical physicist visiting from the
University of Pennsylvania, tried the effects of the radiations on delaying the growth of wheat seedlings. Here one roentgen of neutrons did the damage of 20 r of x rays. Would neutrons prove ten or twenty times as effective as x rays in other biological contexts? "The general question is of more than theoretical interest, for it bears directly on the possibility of using very fast neutrons in the treatment of tumors."[100]
John Lawrence returned to Berkeley early in February 1936 to take up the general question. With the help of Aebersold, the Lawrence brothers cooked some mice with 84 r/m of neutrons, and other mice with 32 r/m of x rays; neutrons killed with a third the dose (as measured in roentgens) needed for death by x radiation. The numbers fell out differently for sarcoma 180. About four times as large a dose of x rays as n rays was required to prevent pieces of tumor irradiated apart from the mouse from taking after implantation. Call the quantity of x rays needed to kill the tumor (mouse) Xt (Xm ) and the corresponding quantities for neutrons Nt (Nm ). Then Nt = (3/4)N m (Xt /Xm ). That is an exciting equation. It says that although the x radiation required to kill a tumor might exceed that required to kill its host, the lethal neutron dose for the tumor might not. The quantity X t /Xm has only to be less than 1.3. Unfortunately, according to the measurements of Aebersold and the Lawrences, Xt /Xm = 3.5. Still, neutrons appeared to hurt tumors more, and the body less, than x rays.[101]
The doctor paid his next visit in the summer of 1936. "Things are humming," his brother wrote the Chemical Foundation, then eager for news relevant to their big commitment to the medical cyclotron. "The [27-inch] cyclotron is in operation daily, hundreds of mice and hundreds of tumors are being killed by neutron rays." John Lawrence and Aebersold repeated the work on
sarcoma 180 with another mouse tumor, obtained from Yale. It took 3,600 r of x rays, or 700 r of neutrons, to kill half the tumor particles before implantation; on healthy mice, 400 r of x rays had the same lethality as 120 r of neutrons. Hence neutrons killed Yale tumors 3,600/700 times, and Berkeley mice 400/120 times, as effectively as x rays. In this case, Nt = (2/3)N m (Xt /Xm ).[102] Numbers were moving in the right direction. The addressee was William Crocker. John Lawrence's preliminary, but "highly significant," results had figured in Ernest Lawrence's declaration to Sproul in late February 1936 of the need for a clinical arrangement like Lauritsen's to test the efficacy of neutrons on human cancers. Now John Lawrence's firm comparative data about mouse tumors helped to convince Crocker to give the clinic. At the beginning of September, Sproul pitched effectively, as follows: "The newly [!] discovered neutron ray . . . seems to provide a means of overcoming the handicap which now limits the effectiveness of the x ray in the treatment of cancer. It appears that it can be used to increase the destruction of cancerous tissue without increasing the damage to the normal tissue." Greatly overplaying John Lawrence's results, Sproul suggested that neutrons might be three times more effective—wreak thrice the havoc to tumors for the same damage to the body—as x rays.[103]
With Crocker's gift secured, the problem of staff for the clinic demanded solution. During the spring of 1936, the dean of the Medical School, Langley Porter, pressed by R.S. Stone to tighten ties with the Laboratory, met with Sproul and Ernest Lawrence for dinner at the Bohemian Club. Subsequently, Porter's assistant, Chauncey Leake, sought appointments for John Lawrence and Paul Aebersold in the Medical School. The business went slowly. As Poillon, himself a physician, had warned, "Medical men are extremely jealous of their prerogatives and . . . even to have a physicist suggest what they might do is received with anything but acclaim." By the time John Lawrence's appointment came through, he had decided to return to Yale; he kept up his work at
Berkeley on visits that totalled about six months during the academic year 1936/37.[104] Neither he nor Stone wished to postpone neutron therapy until the Crocker cyclotron started up. Ernest Lawrence, concerned to show quick progress, agreed. The Lawrence brothers may have been especially, though irrelevantly inspired by the dramatic improvement of their mother under the rays of the Sloan tube. She had long complained of abdominal pain. In November 1937, the Mayo Clinic discovered an inoperable uterine tumor and gave her three months to live. John Lawrence brought her to San Francisco; Stone irradiated her several times with supervoltage x rays; the tumor melted away. Although the swelling may not have been a tumor at all, its erasure by x rays could not but have encouraged the Lawrences to press to make available an agent they had reason to believe would be still more powerful and beneficial.[105]
As a preliminary to its clinical use, the diffuse neutron beam from the beryllium target of the 37-inch cyclotron had to be collimated and directed to a treatment port. Aebersold had the job, which he discharged by rearranging the water tanks of the cyclotron shielding and by lining the beam channel with lead (fig. 8.5). That kept the intensity within the channel almost twenty times that outside it at the port 70 cm from the beryllium target, where the patient received about 12 r/m. Carpenters transmuted a window of the Laboratory into a door opening into a demountable treatment room entirely screening the cyclotron; "the patients will hardly know they are next to such a monster."[106] A parade of physicians, including one from the National Advisory Cancer Council, trooped through the Laboratory during the summer and gave their
Fig. 8.5
Aebersold's arrangement for neutron therapy. The treatment room is at the
left, within the magnet yoke. Not all the water tanks surrounding the
cyclotron are shown. Aebersold, PR, 56 (1939), 717.
blessings to the general work, if not to the therapeutic intiative. Their good judgment pleased and surprised Cooksey. "My opinion of doctors as a whole has risen tremendously." The first patients were exposed on September 26, 1938, just in time for a visit by the NACC's Arthur Compton. Their skin showed effects no worse than those caused by 12 r/m of x rays. Lawrence informed Sproul. "It gives me great pleasure to report an event of historic interest. . . . I personally believe, and my views are shared by my medical colleagues, that this will be the beginning of a new method of cancer therapy which in a few years will be as widespread as that of x rays and radium." What better time to ask for money? $2,000 for power and supplies, $1,400 for furnishings? "We could, of course, slow down our activities, including bringing to a halt the clinical therapy, but in view of the great immediate importance of this pioneering work it would be no less than tragic to do so."[107]
After five months' experience with therapy at the 37-inch, Stone judged that the results of single erythema doses—doses sufficient to redden the skin—gave encouragement for "a complete course of therapy" and hope for "better results than are now being obtained." It would have been difficult to reach a different conclusion as the cyclotroneers began to fish for a beam in the 60-inch cyclotron. The first patient to absorb neutrons from the Crocker cracker, Mr. Robert Penney, received treatment on November 20, 1939 (plate 8.4). A regular clinical program did not begin until the end of January 1940. Then a few tumors vanished. "Dr Stone and John are very enthusiastic about the results." Thus brother Ernest. But John himself would not go beyond the meaningless formulation of the weather forecaster: "[There is] better than a fifty-fifty chance that neutrons are going to be of great value in therapy."[108] He was therefore just better than half wrong when Stone evaluated the program in 1948. Only one of the 24 patients treated at the 37-inch cyclotron in 1938 and 1939 was then alive, and only 17 of the 226 treated at the 60-inch between 1939 and 1943. All but one of the 250 had been considered incurable. The survivors suffered what Stone described as "distressing late effects" that might not have occurred had they undergone x-ray rather than neutron therapy. He judged that he and John Lawrence had overexposed their patients. "Neutron therapy as administered by us has resulted in such bad late sequelae in proportion to the few good results that it should not be continued." Stone's negative evaluation put an end to fast-neutron therapy for two decades.[109]
After much experimentation, treatment of human cancers by neutron rays recommenced around 1970, at, among other places, the Hammersmith Hospital in London, which used a cyclotron constructed in 1952. By 1978 over 3,000 patients had been treated at eleven centers in Europe, Japan, and the United States. The therapy proved effective against advanced, superficially placed
tumors that could be irradiated with little damage to neighboring normal tissue. The experience at Hammersmith through 1984 was that 70 percent of such tumors regressed after treatment with 7.5 MeV neutrons in comparison with 35 percent after treatment with x rays.[110] Stone and the Lawrences had the right idea but the wrong dosage.