Strange Glow

by Timothy J Jorgensen

  ROLLING OUT THE BIG GUNS

  During the heyday of radium therapy, x-ray therapy for cancer had taken a back seat. The cumbersome Crookes tube, with its poorly penetrating x-rays, was no match for radium’s penetrating gamma rays. But all that was about to change. The physicists had a new toy, and the physicians wanted to play with it.

  As we have already seen, the Cavendish scientists had produced a “machine gun” that shot streams of highly accelerated atomic particles, and they used it to split the atom in 1932. This instrument was called a linear accelerator, or simply a linac (pronounced: 'li-,nak),35 because it accelerated the particles in a straight line toward their target. Conceivably, a similar instrument could be used to accelerate electrons at high voltages and, thereby, produce x-rays with higher energies than those that came from Crookes tubes (by this time, more commonly called x-ray tubes). But a linear accelerator was not an instrument that could routinely be used in a medical setting to treat patients, largely because of the difficulty in maintaining stable high voltages.

  All this changed in the late 1930s when physicist Charles Christian Lauritsen (1892–1968) of the California Institute of Technology (Cal Tech) built a sophisticated 750,000-volt transformer for use in his linac research. Lauritsen recognized that the high-voltage transformer might allow medical applications for linacs, so he contacted acclaimed Californian radiation oncologist Albert Soiland (1873–1946), who had a clinic nearby.36 In a scene reminiscent of Grubbe’s first x-ray treatment of advanced breast cancer, Soiland brought one of his patients over to Lauristen’s laboratory for treatment. The man had advanced rectal cancer. The cancer was not amenable to treatment with standard x-ray therapy because the lower energy x-rays would have burned his anus and scrotum, so the man’s prospects were quite grim. Unlike Grubbe’s first patient who died despite treatment, Soiland’s patient was apparently cured. Shortly following treatment with linac x-rays, the tumor shrank away and the patient sustained only minor skin reactions. Two years later, the patient had just a small lesion where the tumor had been.37 The medical community took note.

  Unlike the Crookes tube, however, which was cheap and readily available worldwide when its medical applications were first reported, a linac was an exotic instrument with an enormous price tag. Also, at the time, the radioisotope cobalt-60 had largely replaced radium as the radioisotope of choice for external beam radiation therapy.38 It had many physical and practical advantages over radium, including affordability. Most physicians were quite satisfied with its clinical performance, and they were very comfortable using it. These old dogs were not much interested in the linac’s new tricks, unless linacs became available at prices comparable to cobalt-60 machines.

  In the case of radium, we saw that medical needs drove radium-refining technology to the point that prices dropped substantially, making it financially feasible to even use radium in military equipment such as watch and instrument dials. In the case of linacs, the opposite was the situation. Linac-related technology found utility in World War II, and military research ultimately drove down manufacturing costs to the point where it was feasible to use linacs for medical purposes.

  Specifically, it was radar research that ultimately produced the technological bridge that made medical linacs feasible. As we’ve seen, production of radar equipment was critical to the United States military during World War II, and there was a major need to produce a small radar device that could produce microwaves of very high power. Initially, a microwave radio transmitter called a klystron was invented for this purpose. (It was ultimately replaced by the magnetron that Percy was instrumental in mass producing.) After the war, the klystron technology was applied to linacs. The approach was to use a waveguide—a copper pipe into which electrons were injected—and push the electrons down with microwaves emitted from the klystron. This is analogous to a surfer being pushed along by an ocean wave. The result was a compact and relatively inexpensive linac with electrons traveling near the speed of light, with energies equivalent to 6 million electron volts. At a price tag of around $150,000 ($1,500,000 in 2015 dollars), it would still be a long time before most radiation oncologists would feel the need to have one in their clinic. The radiation oncologists would need to be impressed by what these fancy new toys could do for patients before they were going to invest that kind of money.

  Just as Grubbe knew that the true value of x-ray therapy for cancer would not be appreciated until it was specifically deployed in the patients most likely to benefit (i.e., the early-stage breast cancer patients), the linac needed a patient population in which to show its stuff. Radiologist Henry Kaplan (1918–1984) thought that Hodgkin’s disease victims might represent such a population. Kaplan understood better than most that the most critical factor determining success of cancer therapy was accurately matching the patient to the appropriate treatment. That is, only by understanding the underlying biology of a disease can you most effectively prescribe the treatment. And he thought he understood Hodgkin’s disease biology well enough to match it with a perfectly suited treatment, and that happened to be linac therapy.

  Hodgkin’s disease is a form of cancer of the lymph nodes that most commonly strikes young men.39 It was discovered in 1832 by British pathologist Thomas Hodgkin (1798–1866). He had collected a series of cadavers of young men who had died of a strange disease characterized by enlargement of the lymph nodes in the chest. He did not know it was a type of cancer. Hodgkin presented his finding of this “new” disease to his colleagues and published a paper, thereby recording his primacy in its discovery. But since the disease was uniformly lethal and Hodgkin did not recommend a treatment, his report was largely ignored until 1898. Then, Austrian pathologist Carl Sternberg (1872–1935) was able to show that the affected nodes actually contained cancerous lymphocytes (a lymphocyte is a type of white blood cell), thus identifying the disease as another form of lymphatic cancer.

  Hodgkin’s disease has an unusual and distinct disease progression pattern.40 Instead of randomly metastasizing to distant lymph nodes, as cancer so often does, it progressively spreads along a chain of lymph nodes in linear sequence. This makes it easier for physicians to precisely define the limits of the disease in any particular patient. Yet, the Hodgkin’s disease lymph nodes are often deep in the chest; this meant that lower-energy x-rays, which are poorly penetrating, were ineffective. It was these combined characteristics of Hodgkin’s disease—deep tumors with well-defined locations—that would prove to be the game changer for the linac.

  Kaplan felt that Hodgkin’s disease was highly amenable to linac radiation therapy because it is largely a localized disease and radiation therapy is a local treatment. That is, radiation can only eliminate the cancer localized within the treatment beam. If the cancer has spread to regions outside the radiation beam, the therapy would produce temporary local control, but metastases (i.e., sites of cancer that have spread far from the primary tumor) would ultimately cause treatment failure. Since Hodgkin’s disease is usually localized, Kaplan reasoned that it should be curable. But it would require the higher-energy penetrating x-rays from a linac to do the trick.

  Kaplan capitalized on prior research by Swiss radiologist René Gilbert (1892–1962) and Canadian surgeon Mildred Vera Peters (1911–1993) that suggested Hodgkin’s disease responded well to radiation therapy if the treatment field was extended to include both diseased and neighboring lymph nodes. Complete cures, however, were still elusive due to the limited penetration of conventional x-rays. Kaplan reasoned that if he combined penetrating linac x-rays with Gilbert and Peters’ treatment approach, he would be able to produce cures, provided he chose patients with highly localized disease.

  Kaplan understood that poor staging—the practice of assigning patients to treatment groups based on the stage of their disease—would result in the erroneous inclusion of more advanced-stage patients among the early-stage patients that he intended to treat with the linac. Since advance-stage patients with widespread disease had no hope of a cura
tive benefit from localized radiation therapy, their inclusion would decrease the apparent cure rate of the linac. Consequently, Kaplan took special pains in meticulously staging his patients. He went as far as doing surgical explorations with node biopsies before concluding that the patient’s disease was truly localized and, therefore, amenable to curative linac radiation therapy.

  Although this may sound like Kaplan was simply stacking the deck in favor of his chosen treatment, the fact is that cancer is a very diverse disease, and treatment options are highly variable as well. Mismatching patients with treatments does no one any good. Since the curative potential of radiation is restricted to the location of the radiation beam, the real issue was not whether a particular treatment was good or bad, but whether that treatment had been tried in the right patients. No cancer treatment could be all things to all patients. Kaplan understood this well, but it would take years for many of his clinical colleagues to come around to this realization.

  Kaplan began a clinical trial with his well-defined early-stage Hodgkin’s disease patients and soon found that the linac x-rays were capable of effecting nearly miraculous cures. Within a relatively short time, Kaplan demonstrated that Hodgkin’s disease could be consistently cured with linac x-rays. Soon, 50% of Hodgkin’s disease patients were being cured of their disease, thanks to the linac. As of 2010, 90% are being cured. (The more advanced cases are, of course, less curable, but even for advanced disease, current cure rates now stand at about 65%.41)

  The concept of matching subsets of cancer patients with distinct treatments that target their specific form of disease is now fully accepted as a powerful therapeutic approach, but Kaplan was among the first to fully appreciate this. As such, he was able to reveal the true value of linac x-rays in curing cancer.

  Today, new technologies for defining cancer patient subsets, based on genetic traits and other molecular and cellular factors, are becoming available at a rapid pace. These advances will continue to improve medicine’s ability to define and characterize individual cancers in a highly sophisticated fashion that goes well beyond simply identifying the organ or tissue from which it arose. Significant improvement in outcomes can be expected if such efforts result in better matches between patients and treatments, even if the repertoire of current treatments doesn’t substantially change. But radiation treatment options are continuing to expand.

  Linacs are just the tip of the iceberg. The modern radiation oncologist is armed with a whole host of radiation-producing machines that can be selectively used to suit the circumstances of the disease and the patient being treated. Regardless of the nature of the specific machine, all are designed to better place a radiation dose directly within the tumor, and kill as many tumor cells as possible while sparing normal tissue. The challenge now is how best to use these powerful tools and in exactly which patients.

  Physicians Grubbe, Kelly, Soiland, and Kaplan, as well as the physicists that helped them, were true pioneers of radiation therapy for cancer, and they met with remarkable successes, including some of the first cures for multiple types of cancer.42 From their time to the present, there have been great advancements in both our understanding of tumor radiation biology and the technology used to deliver therapeutic radiation exactly where it needs to be. Radiation therapy for cancer has progressed precisely because radiation physics and medicine have advanced hand in hand.

  Why aren’t all cancers curable with radiation? If cancers were always localized, radiation would be able to cure most of them. Unfortunately, cancer often spreads around the body, making radiation therapy an endless task of finding the cancer and irradiating it before it does damage. The more likely a cancer will spread, the less likely that radiation can produce a cure. In the case of cancer that has spread, radiation therapy needs to be combined with some type of chemotherapy that can circulate through the body and kill distant metastases before they even become clinically apparent.43 Modern cancer therapy amounts to orchestrating an intricate dance between radiation therapy, chemotherapy, and surgery to find the optimal combined-treatment strategy for each individual patient; this treatment strategy is based on both the extent of the disease and the biology of the tumor.

  But even for the cancers that radiation can’t cure, radiation therapy often has an important function. It can shrink the mass of tumors, thus stalling the disease, and, as Grubbe even saw with his very first patient, radiation can also relieve pain.44 So radiation therapy often plays a major role in cancer treatment even when it can’t cure. Currently, nearly two-thirds of all cancer patients receive radiation therapy at some point during their treatment.

  Cancer patients receiving radiation to cure their cancer can experience side effects due to unavoidable irradiation of their normal tissue. Sometimes the side effects are mild, such as skin irritation. Sometimes the side effects are more severe, such as nerve damage. These side effects occur because some normal cells are innocent bystanders that are killed along with the cancer cells. When radiation doses are high enough to kill cells, there is always some risk of such complications. But most often these complications of treatment are localized because the radiation dose is localized, and they usually can be mitigated with medication. Frequently, the side effects go away completely with time. Unfortunately, some linger permanently and are the regrettable price that patients must sometimes pay for the cure of their cancer.

  Most practicing radiation oncologists, however, will never see any of the severe systemic illnesses that radiation can cause (collectively called radiation sickness) because this result is typically produced only when the entire body is irradiated to doses high enough to kill cells (i.e., more than 1,000 mSv to the whole body). On rare occasion, radiation sickness occurs because of some catastrophic accident, such as Daghlian suffered when he dropped the reflector brick on the uranium core during the Manhattan Project, and irradiated himself to a fatal dose. But it wasn’t until the atomic bombs were dropped on Japan, in 1945, that the medical community saw large numbers of people with whole body doses high enough to cause radiation sickness. And then there would be even more lessons learned about how radiation affects health.

  CHAPTER 7

  LOCATION, LOCATION, LOCATION: RADIATION SICKNESS

  We will now discuss in a little more detail the struggle for existence.

  —Charles Darwin, On the Origin of Species

  155 DEGREES

  It’s no small feat to drop an atomic bomb from an airplane and not fry your own ass in the process. Yet this was the charge that Lieutenant Colonel Paul Warfield Tibbets (1915–2007) was given. He was to pilot a B-29 atomic bombing mission over a yet to be determined Japanese city, and return the plane and crew safely home.1

  Tibbets’s task was to design and fly a safe mission. But what is considered safe? The US airmen were not kamikaze pilots. The odds needed to be in the favor of the plane and its crew for a mission to get the command to go ahead. How much in their favor? During World War II, a mission with a risk level of no worse than one in ten (i.e., no more than a 10% risk of plane loss) was thought to be safe.2 This would be considered a high level of risk under most circumstances, but not during a war operation.3 Of course, a precise risk calculation for the very first atomic bombing mission was not possible. But Tibbets had many successful bombing missions under his belt from his prior service in the European and North African war theaters, so any flight plan in his hands typically fell well within the one-in-ten risk line. Although he couldn’t precisely measure risk, Tibbets knew how to minimize it.

  Tibbets, an expert on B-29s, knew them to be mercurial beasts. At lower altitudes their performance was spectacular. At high altitudes, however, their engines tended to overheat during long trips, and their steering suffered when overloaded. To deal with this, he planned to fly most of the distance between his base on Tinian Island in the South Pacific and the bombsite in Japan at the relatively low altitude of 9,000 feet (2,700 meters), and then climb to 30,000 feet (9,000 meters) for the final approach.4 Thirty-t
housand feet was a compromise altitude—high enough to minimize the probability of getting shot down by ground artillery, but not so high that the thinness of the air interfered with control of the plane’s flight during the bomb drop. Tibbets also planned to strip the plane of all armaments but its tail guns, reducing the plane’s weight by about 7,000 pounds (3,000 kg), thereby allowing the plane to better accommodate the added weight of the 9,000-pound (4,000 kg) atomic bomb. The weight reduction would also increase the plane’s flight speed. Tibbets similarly knew that the lighter weight would improve the plane’s maneuverability and, most importantly, tighten its turning radius. Since there was no way an overweight B-29 could win an all-out dogfight anyway, they might as well dispense with the heavy guns to increase the flight speed and let the tail gunner cover the plane’s rear as the pilot tried to outrun its attackers.

  Still missing from Tibbets’s bombing plan was a strategy for a safe return to base. Scientists had told him that a minimum safe distance would be eight miles from the bomb’s hypocenter.5 The plane’s altitude would provide some of that distance in the form of vertical height. (30,000 feet is nearly six miles of altitude.) But the rest would need to be provided by horizontally fleeing the scene as fast as possible. A little trigonometry told Tibbets that, at 30,000 feet, he needed five miles of horizontal distance (ground distance) to produce a slant-line distance of eight miles between the plane and the target site. So Tibbets had to get the plane five miles (of ground distance) away from the target site as fast as possible. Allowing that the jettison of the bomb would lighten the plane by 9,000 pounds, thereby further increasing the plane’s flight speed, and given the limited time he had to flee the area (43 seconds between bomb drop and detonation), he calculated the maximum ground distance he could achieve as six miles. Safe by war standards, and with a mile to spare!