By Theodore Phillips and Arjun Sahgal
The following interview of David Larson, MD, PhD, FASTRO, was conducted on July 1, 2016, by Theodore Phillips, MD, FASTRO and Arjun Sahgal, MD.
Theodore Phillips: Let’s start with where you were born.
David Larson: I was born in Astoria, Oregon, and when I was four we moved to El Cerrito, California, next to Berkeley. My father was a junior high school science teacher and also a part-time carpenter. During World War II any undrafted able-bodied male could show up at the Astoria shipyards and immediately be signed on as a journeyman carpenter provided he could swing a hammer, which my father could. Later on, after the war, and when schools were not in session such as during summer vacations, he worked as a carpenter. He was also a leader of Audubon field trips throughout the West, and he often worked summers as a naturalist in California State Parks. My mother taught high school typing, shorthand, dictation and business subjects.
I was the product of an observant Mormon family. I have one older brother and three younger sisters. We went to El Cerrito public schools and my parents put a great deal of emphasis on education. My father earned a master’s degree, my brother a Stanford MBA, two sisters PhD’s, another sister a master’s degree and I a master’s, PhD and MD. Collectively, eight post-graduate degrees. Our parents gave us the freedom and encouragement to determine our own futures, which I have always appreciated.
Theodore Phillips: So your family was Mormon. I didn’t realize that, David. Had they migrated there from Oregon originally? Or were they originally from Utah?
David Larson: My father was born in Utah, but spent the majority of his life in California. My mother was born in Illinois and her parents were well-to-do farm owners. But during the Great Depression they lost everything and moved to Oregon. My father went to college in Oregon and that’s where he met my mother, in Corvallis.
Theodore Phillips: That’s interesting. Can you tell us a little about your high school?
David Larson: Sure. Well, I went to El Cerrito public schools, including Harding Grammar School, Portola Junior High School and El Cerrito High School, all of which continue to function. I was active in high school government – the president of our high school senior class, our school spirit organization and a high school social fraternity. I loved intramural basketball and I was a competent skier.
When I was in high school, a family friend who worked at Lawrence Berkeley Laboratory running the LBL Cyclotron and Bevatron took me on a lab tour and I decided then that I wanted to study particle physics, not for a moment expecting I would eventually do exactly that at Lawrence Berkeley Laboratory (which I’ll get to later). Anyway, I still keep up with about 30 or 40 of my high school colleagues. And we have a yearly reunion at a restaurant in Berkeley, the second weekend of every January, very nostalgic, very nice. That briefly summarizes some of my pre-college experience.
Theodore Phillips: Now, where did you decide to go to college? Did you have a choice? Did you have different options in that?
David Larson: Realistically I didn’t have much choice, though it worked out very well. I could either go to UC Berkeley and live at home, since money was scarce, or go to a local junior college and live at home, or go get a job. So I decided to go to UC Berkeley and I majored in physics. I was an honor student. I received some sort of award for being the graduating class’s top undergraduate physics student, and I still keep up with some of my college classmates after all these years.
As an undergraduate, I was an avid skier in the Sierras (and later in Canada, Europe and throughout the U.S.). I briefly joined the UC Berkeley crew, a great sport for tall athletes. I was an avid backpacker both in high school and in college and thereafter, with numerous hikes in the Sierras and also in Alaska and Nepal. I was a summer student one year at the Naval Radiological Defense Laboratory at Hunter’s Point in San Francisco, and another year I worked as a summer student at Brookhaven Laboratory in a group doing particle physics.
Theodore Phillips: What year were you at NRDL, Dave? I didn’t realize that either. That’s where I spent my two years in the Navy. I was at that lab.
David Larson: I think it was in 1964, as a summer student. As you may recall, to enter the facility, an eight-story windowless building, you’d show your pass, and there would be guards with holstered guns at the entrance gate to let you in. One day I accidently showed a fishing license rather than my pass but they let me in without noticing. A small security flaw, I suppose.
Theodore Phillips: Well I was there from ’63 to ’65 as an active duty in the Navy. Do you remember who you worked for? Whose lab you were in?
David Larson: All I can remember is that a lot of work was classified, though the work I was doing was not classified. I helped organize balloon weather data, wind speed and temperature at different altitudes, humidity and so forth, for the days before and after atomic explosions at Bikini or in Nevada. So I was helping gather up and organize weather data. I can't say this was high-powered work. I mean, after all, I was just a student. What did I know?
Theodore Phillips: There was a major activity there because they were charged with predicting what would happen to fallout if there were a nuclear war. But you were working on that.
David Larson: I guess I made some very minor contribution to that effort.
Arjun Sahgal: David, I guess at that time there was a lot of student uprising also especially at Berkeley, right? What was kind of happening around you while you were there?
David Larson: Well, it’s interesting. That was the era of the Free Speech Movement and Mario Savio. I was a pretty good student, not necessarily in high school but certainly in college I was a good student, very dedicated. My friends and I often studied well into the night at one of the on-campus libraries. At that time there was round-the-clock campus activity, lots of demonstrators, lots of police, lots of signs, lots of speeches being given. Mario Savio gave excellent, excellent, speeches. He really got the crowds behind him. One day there was an Oakland Tribune front-page picture of me, the interested student listening to Mario Savio. Years later when I was a medical intern at UCSF, a patient was admitted with possible bacterial endocarditis, and it happened to be the Free Speech Movement leader, and I took care of him for several weeks.
Theodore Phillips: Wow.
David Larson: Let me tell you about grad school. In 1965 I went to Columbia on an astrophysics fellowship, though I had also been offered a fellowship at the University of Chicago. During 1965-66 I applied to Columbia’s College of Physicians and Surgeons and was accepted for 1966. So I had three possible choices for 1966 and beyond: Columbia/astrophysics, Columbia/medicine or Chicago/particle physics. In the end I said no to medical school (at least at that time). Instead I went to the University of Chicago. I got a master’s degree in particle physics at Argonne National Laboratory, and then I did my PhD work at Lawrence Berkeley Laboratory with a physics group from the National Research Council of Canada, Ottawa University and the University of Chicago, and funded by the National Science Foundation. At that time we occupied some of the very same LBL lab space that radiation oncologist Joe Castro was occupying, from which he and Ted Phillips ran the UCSF particle therapy group at LBL, using at first the 184 cyclotron to deliver helium ions and later the Bevalac to deliver helium, argon, neon and carbon ions. I met Joe at that time, of course, but never suspected then that I would one day join him as a fellow physician and colleague on the UCSF Radiation Oncology faculty.
After completing graduate school I joined a very productive Cornell/Harvard experimental elementary particle physics group in Ithaca at Cornell University, again funded by the NSF. I performed experiments and designed and built multiwire proportional chambers and detectors including the inner drift chamber of the colliding beam facility. I was there for seven or eight years. One of those years I lived in the home of physicist Hans Bethe, who was awarded the Nobel Prize for figuring out the physics of energy production in stars.
Theodore Phillips: Were you a postdoc that whole time, Dave, or were you then faculty?
David Larson: It was a permanent non-faculty research position, and I loved it, and it was a little bit courageous to eventually apply to medical school, and if accepted to leave something I knew I enjoyed for something I might or might not enjoy. In any case I was accepted, and I enjoyed medical school to some extent. There were some classes and rotations that I liked, some not so much. I was attracted to internal medicine, pathology, radiation oncology, anesthesiology, nuclear medicine and radiology. I wasn’t attracted to the surgical specialties. A most significant learning experience for me, one that solidified my interest in radiation oncology, was when I went to Los Alamos on an elective rotation to learn the basics of pion radiotherapy with radiation oncologist Steve Bush. The principles of pion radiotherapy are still solid, but the cost to produce pions greatly exceeds that to produce protons or carbon ions.
Near the end of medical school students were of course making decisions about where they were hoping to do their internship, as was I. Although the Los Alamos physics division offered me an attractive job to help design a new accelerator for materials research, I entered the match and I was accepted at UCSF. During my internship year I was recruited heavily by the UCSF Department of Medicine to change my upcoming PGY2 year from radiation oncology to internal medicine. Nevertheless, I chose radiation oncology with Sam Hellman at the Joint Center for Radiation Oncology.
Theodore Phillips: Could you go back a little bit and say something about where you went to medical school, and why, and what happened to that program?
David Larson: My medical school was the University of Miami School of Medicine. I was 39 years of age when I entered medical school and 41 when I graduated. At that time the University of Miami had a separate small medical school program that had been running for 15 or 20 years, based on the assumptions that if you had a PhD in science, they could successfully put you through medical school in two years rather than four, and that such graduates might likely end up in academic medicine. The substance and exams of the two-year program were similar to that of their normal four-year program. I became part of a class of about 30 students and I was class president. I graduated after two years, at the age of 41, having not slept much for two years. The school’s motivating idea at the time was that America needed more scientists in medicine in order to accelerate scientific progress, i.e. “Let’s select people who have a PhD, put them through medical school quickly, and get them out there in academic institutions.” From today’s perspective I’m not sure about the logic of all that but for many years that was the program. For me it worked out well and thereafter I went on to good institutions for my internship and residency and professional work.
Theodore Phillips: Do they still have that program?
David Larson: They don’t have that program. The person who developed that program, an internist at the University of Miami, died some years ago and the program died as well.
Theodore Phillips: At the end of your internship, like from what you said, you had already decided to go into rad-onc. Is that true?
David Larson: Yes, I had decided to go into rad-onc even though during my internship I was attracted to internal medicine. Nevertheless, I matched with the Joint Center for Radiation Therapy, so after internship I headed off to Boston.
Arjun Sahgal: Dave, you were also in that time period where all of the illnesses surrounding HIV were happening, also in San Francisco, right? You were kind of at that phase where new illnesses and weird things were happening, correct?
David Larson: That’s absolutely correct. In fact, there was a definite excitement about what was being learned every day about the tragedy of HIV and AIDS. I was interning at then one of the main HIV research centers in the world, at San Francisco General Hospital, one of the hospitals that medical interns rotated through at UCSF. Paul Volberding, one of the early leaders in the United States in AIDS research, was there and I saw patients with him. I saw lots of affected patients at the start of my internship year, when nobody knew what was going on, and by the end of my internship year, it had been given a name, AIDS-related illness, and so forth. And when I got to Boston for PGY-2 I was surprised that most physicians were not up to speed on what this disease was. It took probably a year or two after my experience in San Francisco before it started becoming a major research focus throughout the U.S.
Arjun Sahgal: So then you entered the radiotherapy residency program at the Joint Center?
David Larson: Yes, and it was pretty interesting. Of course at the time it was a three-year program rather than today’s four-year program. Sam Hellman was chair, although he left for Memorial Sloan Kettering part way through my residency, and he was an excellent, excellent, excellent teacher. In my third year of residency I was the chief resident but it turned out that the Joint Center had a staff shortage. Jay Harris, the interim chair, called me into his office office one day and said, “We have a shortage of instructors, so would you be willing to be an instructor? We’ll double your salary. We’re not going to give you a resident or student. You’re going to specialize in head and neck tumors. You will be an attending, with attending privileges. But you’ll work alone.” I thought, “Geez, that’s a pretty good deal.” So, even though I was only in my third year, I became an instructor, and saw and treated patients on my own. My co-residents in that third year were Jeff Schneider, Roger Anderson and Mark Brenner. Residents one year ahead of me were Joe Imperato, Tom Sheldon, Alan Forbes, Abe Recht, Elliot Rosen, TJ Fitzgerald and Howard Halpern. Jay Loeffler, with whom I have frequently collaborated, was a resident one year behind me. John Flickinger, also in my year, was across town at MGH and he and I and Jay often collaborated. So, a lot of good people as residents. My main mentor and role model was Sam Hellman. But I was also positively influenced by John Chaffey, Jay Harris, Chris Rose, Les Botnick, Nancy Tarbell, Bob Cassidy and Wendell Lutz. I often looked over Wendell Lutz’s shoulder late evenings as he and neurosurgeon Ken Winston were modifying a linac to do radiosurgery.
Arjun Sahgal: Is that when you got kind of interested in or dedicated towards radiosurgery?
David Larson: Yes, that’s certainly where I developed my interest. I noticed Wendell Lutz and Ken Winston working together late every evening. They were developing single fraction linac radiosurgery, something that seemed to be at odds with the 4 R’s of radiobiology. After residency, when I joined the UCSF faculty, I asked Wendell if he’d share his linac radiosurgery design plans, and he did so without hesitation. So with the help of UCSF physicists Vernon Smith, Mike Schell, Cliff Ling, and Bruce Lulu, and the support of Ted Phillips, we put together a radiosurgery linac and wrote our own Fortran dosimetry software, and we used the system from 1988 until 1991.
UCSF was one of the initial radiosurgery programs in the country. But others deserve credit as well. Boston neurosurgeon Ray Kjellberg, UC Donner Lab internist John Lawrence and LBL radiologist Jack Fabrikant contributed to the early development of American particle radiosurgery, followed by Jay Loeffler’s linac SRS in Boston in 1986, Dade Lunsford’s Gamma Knife in Pittsburgh in 1987, and my linac in San Francisco in 1988. I had been recruited by Ted Phillips to do particle therapy with Joe Castro at LBL in Berkeley but I wanted to remain in San Francisco at least for a while to learn more about X-ray therapy and it turns out I remained in San Francisco for my whole career. Initially I had a special focus on breast cancer because during residency in Boston I had seen a lot of breast cancer patients with Jay Harris, and I felt pretty confident about that. But there was a guy at UCSF, one of the breast cancer surgeons, who found it hard to recommend radiation (although years later he changed his tune) and found it hard to ask us to see his patients, and I thought that that was going to be too much of a problem to work with such a person. So I decided to concentrate on central nervous system radiation oncology. So early in my career I worked pretty closely with a very productive and delightful team, including Ted Phillips, Steve Leibel, Glenn Sheline, Phil Gutin, Charlie Wilson, Victor Levin and Mike Prados.
Theodore Phillips: Glenn was about to retire so we really wanted you to become the new Glenn Sheline, the national leader in brain tumor radiotherapy. You accepted that as I remember.
David Larson: Yes. Well, it turned out my career has worked out very well along those lines, and in fact you were very supportive of all that. You were a great chair although since then the radiation oncology chairs haven’t worked out nearly as well.
But in terms of radiosurgery being one of my main interests, I early on could not really see the logic of whole brain radiotherapy for everybody with brain mets. I always thought it was the Senator Joe McCarthy theory of brain mets: that there are communists (or mets) everywhere even if you can't see them.
Theodore Phillips: How did the radiosurgery program develop? Did it take off like a rocket or was it slow to develop?
David Larson: I would say it developed at a moderate pace. I ended up treating somewhere around 120 patients between 1988 and 1991, over three years. So not a huge number of patients but enough so that I could be on top of potential single fraction complications, of which we had very few, as it turned out. I was pretty much plugged into other radiosurgery departments around the world. I and many other radiosurgeons favored radiosurgery dose distributions over standard radiotherapy dose distributions, given the latter’s unneeded large margins, especially unneeded for non-infiltrating targets such as meningiomas, acoustic neuromas, brain mets and AVM’s.
Fractionated dose distributions and immobilization techniques used at that time were rudimentary by today’s standards. I knew that the 4 R’s argued for multiple fractions, but I also knew that most radiosurgery targets have no normal tissue within them, and thus two of the 4 R’s (repopulation and repair of sublethal damage) must be of lesser importance given good radiosurgery dose distributions and good immobilization. Nevertheless, clinical affirmation of potential radiosurgery advantages had to develop over time.
In 1987 we modified a linac using Lutz’s plans, and I attended the first U.S. Radiosurgery Congress in December, 1987, in Boston, which had over 100 attendees even though only three of them, Ladislau Seiner, Jay Loeffler and Dade Lunsford, had treated anybody with X-ray or gamma ray radiosurgery. I saw my first radiosurgery patient soon thereafter, in March of 1988, a patient with slurred speech and subarachnoid hemorrhage from a left parietal arteriovenous malformation referred by neurosurgeon Charlie Wilson. Charlie thought surgery would be dangerous, so I delivered 1800 cGy at the 80 percent isodose surface using two isocenters. The patient had complete angiographic obliteration in three years, and I’m still in contact with him. He has a normal physical examination almost 30 years later. It was a very encouraging first effort.
Theodore Phillips: Jack Fabrikant had been treating those lesions with helium ions in Berkeley, hadn’t he, prior to the linac radiosurgery era?
David Larson: Yes he had been, starting in the 1980’s, using a multifraction Bragg peak technique. At the time, he didn’t call it radiosurgery because there was this convention that you couldn’t call it “radiosurgery” if it was more than one fraction, but by today’s standards it certainly was radiosurgery. And much earlier Ray Kjellberg in Boston was treating AVM’s with single fraction Bragg peak protons, beginning around 1961. And John Lawrence at LBL treated pituitary indications with multifraction cross-fired non-Bragg peak helium ions, beginning in 1954. Those three people, non-radiation oncologists, are sometimes left out of the history of radiosurgery, but they really should be included.
Arjun Sahgal: Dave, you went through I guess the transition between CT and MRI also in radiosurgery, correct?
David Larson: At UCSF the transition from non-CT based to CT-based treatment planning for brain tumors took place in 1981, well before we were doing radiosurgery. I have to mention a paper written by Brian Goldsmith, one of our residents, and co-authored by Charlie Wilson, Bill Wara and me. The idea was to look at all of the meningioma patients that had been treated at UCSF over the years. There had been several publications from UCSF and other institutions showing that the local recurrence rate after radiation therapy for meningioma was somewhere around 20-30 percent. That seemed pretty high, and when we looked at our data we found that the recurrence rate was indeed 20-30 percent at five years for patients planned and treated before 1981, but only 2 percent if treated in the CT-based planning era, after 1981. So we published that, and I got quite a number of phone calls from colleagues around the U.S. saying that that couldn’t possibly be true. But those data were soon replicated by many groups. Of course in retrospect it makes no sense that you could have low recurrence rates without good targeting. So that was a great lesson for all of us.
Theodore Phillips: When did you switch to using MR for planning in radiosurgery?
David Larson: Well I’m not sure. We used only CT-based planning during our linac SRS period, 1988-1991. We began using a Gamma Knife in 1991. I suppose we used MRI planning for SRS in the early 1990’s. I recall that by 1991 we were using MRI to follow volumetric changes in gliomas after fractionated radiotherapy.
Arjun Sahgal: Ted, maybe should we talk about the story of how UCSF got the Gamma Knife?
Theodore Phillips: Yes, what happened, we decided that we wanted to do everything possible that was new and radiosurgery was one of them. And then I think that the surgeons were so happy with Dave’s linac radiosurgery program, they pushed to get the Gamma Knife. Is that right, Dave?
David Larson: Well, yes. I think they did push to get it. But here’s a funny story behind it. So one day I got a call from the secretary of the CEO of the hospital. Who was the CEO back then anyway, Ted?
Theodore Phillips: It was Bill Kerr then.
David Larson: Oh yes, that’s right. So Bill Kerr’s secretary called me and said, “Mr. Kerr would like you to be at a meeting in his office at 7:00 tomorrow morning.” I asked what it was about but she said she didn’t know. So I dutifully showed up the next morning at 7:00, and in attendance were Bill Kerr, Charlie Wilson, neurosurgeon/businessman Ernie Bates and several others, and Bill Kerr said, “Tell us about radiosurgery.” So I told them we had this nice modified linac downstairs and I told them what radiosurgery was all about and so forth. I spent about 10 minutes. Then they said, “Well, should we buy a Gamma Knife?” My opinion was, “Well, no, I wouldn’t buy a Gamma Knife because it costs a lot of money, and we could do everything with our apparatus downstairs that you could possibly do with a Gamma Knife.” They asked a few questions, and then they excused me, and a couple of days later, Bill Kerr’s secretary called me up and to say that Bill had asked her to call me to thank me for explaining about radiosurgery and she said, “And based on your presentation we’ve decided to get a Gamma Knife.”
Theodore Phillips: I would assume it was Charlie who decided to get a Gamma Knife.
David Larson: I think that’s it, yes, and it was a good decision.
Theodore Phillips: Charlie Wilson was extremely influential at UCSF at that time because he filled an awful lot of beds.
David Larson: Yes, he certainly did. He was very successful. So anyway, I treated my first SRS patient in early 1988, and I treated another handful of patients during the months preceding that year’s annual ASTRO meeting. Bob Cassidy called me up and asked me if I would give an educational course at ASTRO in 1988. At the time, they didn’t call them educational courses; they called them refresher courses. So I gave the first SRS refresher course in 1988, in a room crowded with 400 attendees, standing room only. Everybody was interested in SRS. But the word “refresher” was a bit of a misnomer because since there was so little known about SRS, how could you refresh anybody? I also gave the same course in 1989, when there was more information available, so the first two ASTRO SRS educational courses were done by me, and there was great individual clinician interest and great ASTRO societal interest in this new thing called SRS.
A few years later I had a 12-month sabbatical. That was in the days when sometimes Ted gave us prolonged sabbaticals. I spent 12 months at the Karolinska Institute, not so much to learn about radiosurgery but to learn about stereotactic body radiotherapy, which didn’t even have a name at the time. Karolinska physicist Ingmar Lax and oncologist Henric Blomgren had published a report with a very high rate of local control for various diseases, such as liver tumors and liver mets and so forth, using a homebuilt modified linac for radiosurgery to sites other than the brain. So I learned how to do that, and I came back and I treated more than 100 patients between 1994 and 1995. And it was probably three years before anybody else in the U.S. was doing body treatments, later to be called stereotactic body radiotherapy or SBRT.
Theodore Phillips: What was the dose fractionation schedule for that, Dave?
David Larson: I usually gave three fractions and I gave pretty conservative doses for most of the lesions, to avoid complications. I treated much more conservatively than what we would do now, probably about 600-700 cGy x 3, or something like that. So pretty conservative.
I should mention that Bob Timmerman visited UCSF in the early 1990’s and we worked together. He was very interested in SBRT. In fact, I looked at that visit by Bob as something that influenced the development of his career. He’s gone on to be one of the world leaders for SBRT and so-called ablative therapy. This term “ablative therapy” to me is a little bit of a misnomer. It implies that patients with early breast, prostate or head and neck cancer, for example, who have been cured with standard fractionation, hadn’t had “ablative” therapy. Well, it had to be ablative because they were cured. How could it be more ablative? Anyway, “ablative” is now a widely used standard term and it often refers to body radiosurgery.
Theodore Phillips: Let me ask you a question. I’m really interested in the history of the beginnings of SBRT. Do you think it was mainly due to the work that was being done by you and Timmerman and all, or did a big impetus come from the introduction of the Cyberknife?
David Larson: Timmerman made many important contributions lasting over the long term. But I think that what I did and Timmerman did didn’t have nearly the short-term impact that the Cyberknife had. The Cyberknife folks proposed the term “staged” radiosurgery, terminology that to me made no medical sense. If you do staged surgery, for example, you don’t do the identical surgery multiple times on a patient. You remove what you didn’t remove the first time, for example, and perhaps with a different approach. But initially, “staged” radiosurgery involved delivering exactly the same dose with the same dose distribution a number of times. Anyway, Cyberknife had launched a major lobbying effort to develop codes for up to five fractions, and I think the successful development of those codes enabled reimbursement for multiple fractions, and that in turn got us into SBRT in a big way over the short term by dramatically increasing Cyberknife sales.
Arjun Sahgal: But you saw the development of the machine with John Adler, right? What was the feeling at that time?
David Larson: John had trained in Boston and then had gone to the Karolinska Institute as a fellow and had seen the Gamma Knife in action, and he decided when he got back that he was going to design a device which didn’t require an invasive stereotactic frame. That was his whole SRS notion – that an invasive stereotactic frame should not be required.
I remember early on visiting John in Silicon Valley where he had a tiny ball bearing target mounted on a tripod and he had a laser, instead of a linac, mounted on a robot. This robot was rapidly arcing over most of the solid angle, with the red laser beam continuously pointing at and reflecting off the ball bearing. It was very impressive to see that, and it was especially impressive that one could put more than a quarter ton of linac on the robot and it would still be just as accurate.
Theodore Phillips: Dave, were you surprised by how efficacious this hypofractionated radiosurgery to the other lesions outside the brain has proven to be?
David Larson: Actually, I have to say that the only part that’s been surprising to me is how well it’s taken off. I wouldn’t have predicted it would become nearly as common as it has, because early on several respected clinicians thought it was an exercise in futility, because of the 4 R’s. One even said, “Anything you can treat with n fractions, I can treat better with n+1 fractions.” But it doesn’t surprise me at all that it works as well as it does. As long as there’s no normal tissue in the target, the 4 R’s are less relevant, especially if the dose to a very small volume of normal tissue beyond the target is very small. So it really depends on having a very steep dose gradient, so that complications, if any, are going to be confined to a small rim of normal tissue.
Theodore Phillips: But do you think the 4 R’s of radiobiology that were championed 30 years ago has now been disproven as being unimportant in terms of tumor control?
David Larson: Actually, I don’t think they’ve been disproven. We’re starting to come full circle. There was initially the notion that it’s not “radiosurgery” if you do more than one fraction. If you do two fractions you can’t call it “radiosurgery.” So everybody at first was doing one fraction, despite the 4 R’s, and despite some criticism.
What we’re learning now is that for large tumors you are much better off doing perhaps three fractions. Larger tumors, I think, usually have a fair amount of hypoxia. If you have hypoxic tumors, you’re probably better off with two or three fractions rather than one. Reoxygenation makes sense. There’s a recent paper from Rome showing better control for larger mets treated with three fractions compared to smaller mets treated with one fraction. They compared a number of patients, matching them up very well in terms of gender, age, location and so forth. The only thing they didn’t match up was tumor size. It turns out larger tumors with three fractions had increased local control and decreased radionecrosis compared to smaller tumors given one fraction. This tends to at least partially support the 4 R’s.
Now, all the radiosurgery apparatus manufacturers build SRS apparatus in such a way that one can accurately deliver more than one fraction. I think as time goes by we are going to see more and more patients get perhaps two or three fractions. Whether you’d do even better yet with ten fractions is an open question. My guess is probably not much better, at least for brain and spine.
A bit of history: recall that Baclesse and Coutard in Paris showed that the peak of the therapeutic ratio was at 6-8 weeks of fractionation for breast and head and neck cancer, with longer courses having lower cure rates and shorter courses having higher complication rates. With modern imaging and targeting the peak has certainly moved to shorter courses for several indications. For example, clinical outcomes for small meningiomas are the same for 30 fractions or 1 fraction. And local control rates for brain mets is at least as good or better with SRS, compared to WBRT, and SRS certainly avoids the neurocognitive toxicity of the latter.
Theodore Phillips: The big fractions, I think, are important because they get you down off the shoulder of the survival curve. It’s really like high LET.
David Larson: That’s right.
Theodore Phillips: Twelve Gray per fraction, you're doing just like you were doing it with carbon. I think Arjun, did you want to have Dave talk some about the history of the turf wars in radiosurgery?
Arjun Sahgal: I think it would be great. So Dave, I think it was while you were president of ASTRO that kind of this turf war with neurosurgery was starting to happen about signing off Gamma Knife plans or who would own the turf. Because in some countries neurosurgeons do it without a radiation oncologist, and in other countries it may be the other way around. But that wasn’t the case in the United States, correct?
David Larson: There were two turf war issues at different times. I’ll try and speak about them separately. The first one started in 1989. There was a recently installed Gamma Knife in Pittsburgh, and there was a radiosurgery linac in Boston. And speakers and attendees at conferences, around 1989-1993, when radiosurgery was starting to proliferate, made claims of ownership of the technique. A neurosurgeon would claim it was really a neurosurgical technique, and radiation oncologists would claim it was really a radiation oncology technique.
Well, in the midst of this, in 1991, ASTRO asked me to be head of a task group to define what radiosurgery is. And so I recruited several people - Frank Wilson and several radiation oncologists and several physicists, and we began producing a document defining what radiosurgery is and who should be doing it and so forth.
Well, when neurosurgeons learned of this they formed their own task group to write a competing document. Well, it seemed to me that this was going to be really counterproductive because, after all, what we all wanted was that if you designed and delivered a treatment, you should get paid no matter what your specialty. So one day I called up the neurosurgeons and suggested we develop a joint document, and they agreed to that. In 1993, about 15 coauthors - radiation oncologists, physicists and neurosurgeons – published that joint document in the IJROBP describing what radiosurgery was. It was at that time single fraction treatment, and it required various personnel, including physicists, nurses, radiation oncologists, and neurosurgeons, and so on. So that’s what radiosurgery was defined to be. And that identical article was published in 1994 in one of the neurosurgery journals and it had the blessing of ASTRO, AANS, and CNS. The only difference between those two articles was the order of the authors. I was the first author in the IJROBP, neurosurgeon Dade Lunsford was the first author in the neurosurgery journal, and that was one of those rare situations where the editors published the identical article twice. That went a long way to defining who does it and who gets paid. And of course in other countries they may do it differently, but that’s the history of how that happened.
Then there was this second thing that happened in about 2001 when I was president of ASTRO, and that was when the neurosurgeons were proposing that “staged” radiosurgery ought to be something that gets reimbursed. I represented ASTRO when ASTRO, AANS, and CNS leadership met at the airport in Chicago for a day to hammer out an agreement. I remember something that I thought was pretty humorous. I was sitting across the table from the president of one of the neurosurgery societies, and he was very much in favor of the notion that any number of stereotactic fractions ought to be billed as radiosurgery. So I remember having this conversation with him. I said if you did one fraction would you call it radiosurgery? He said, yes. What about two? Yes. What about three? Yes. And I went all the way up to ten, and every time I said a number he’d say, yes, that should be called radiosurgery. I said, what about 30 fractions, and he said, yes. Anyway, we finally agreed that one to five fractions would be called radiosurgery and would end up having an appropriate code. So we resolved that problem also.
Theodore Phillips: Would that be about the time that the Cyberknife was developing their five fraction units and so forth?
David Larson: Yes. The Cyberknife people worked with a well-connected lobbyist in Washington to help sway the argument for “staged” radiosurgery.
Theodore Phillips: I assume, Arjun, you never ran into this kind of problem in Canada. Is that correct?
Arjun Sahgal: No. Well we do have a little bit. It was interesting because when we started the Gamma Knife program, the neurosurgeons felt that they had to sign off on it and there was no law or rationale for that. In fact, we said there’s no need for you to sign off on it. And so that has kind of propagated, but there’s still a lot of push and pull from them to have ownership in this way. Was it tense at that time, Dave, when you were dealing with them or was it amicable or what was the tone like?
David Larson: It was sometimes pretty tense. You sometimes heard some pretty screwy arguments. In fact, at one conference a well-known neurosurgeon managed to keep a straight face at the podium while making the following argument, which I paraphrase: “Radiosurgery is a surgical procedure and here’s why: because what the surgeon does is impart kinetic energy to his arm and his hand and ultimately to the scalpel to remove a tumor. So the surgeon therefore is the most qualified person to apply energy in the form of radiation dose.” I thought that was a pretty silly analogue.
Arjun Sahgal: Yeah. And there were some episodes in the U.S. where they ignored the radiation oncologist and just performed the procedure and there were repercussions, correct?
David Larson: Well there was one U.S. Gamma Knife facility where the neurosurgeons decided they were just going to do treatments without telling the radiation oncologists. The NRC heard about that and they came and temporarily shut down the program. So from my standpoint, the original document that we published in 1993 and 1994 still holds (except now it is 1-5 fractions, rather than just one fraction). So if you were to do it on your own and have a complication there would be no shortage of people who would say it was not the standard of care to eliminate one of the specialists.
Theodore Phillips: Well, Dave, maybe we should move on now to your work with ASTRO and particularly the Gamma Knife Society. First, tell us about what you did for ASTRO.
David Larson: Well, ASTRO was great. I really enjoyed my participation. During my term as president of ASTRO, there were several things that happened. We developed a new long-range five-year plan. Of course, ASTRO does this periodically as they should, but we developed a new five-year plan. We also completely overhauled the governance of the society to have council structures rather than just a bunch of committees. That was useful. We also, during that time, decided that we needed to move from a sort of reactive kind of an organization to a truly proactive organization. That’s when we hired Laura Thevenot as the new CEO, and that worked out very well. A lot of activities during the year that I was the president of ASTRO.
Theodore Phillips: That was the first time ASTRO ever had a full-time director, a salaried professional running the Society. Was that the beginning of that?
David Larson: No. Frank Malouff had been doing it for a number of years as a fully paid, full-time professional.
Theodore Phillips: Oh, I see. Okay. Any other comments about your time at ASTRO?
David Larson: Well, when I’d been nominated to run I had to think about how prior ASTRO presidents Dave Hussey and Chris Rose had spent a lot of time going back and forth to ASTRO headquarters, and I wondered if I could be effective, if elected, without going to Washington as often. It turned out that it wasn’t really necessary to go all the time and do everything myself. If you have the right people in the organization, and we did, you can do most things through phone calls and it worked out well in that sense. Beyond that, I was later honored to receive the ASTRO gold medal.
Arjun Sahgal: Around that time, was the ISRS actually starting because you were also the president of ISRS, right?
David Larson: Yes, I was president of ISRS. That worked out well also. Not as broad an organization as ASTRO, but lots of people around the world belong, and they have meetings every two years, and I usually attend.
Theodore Phillips: Is the International Society for Radiosurgery the same as the Leksell Gamma Knife Society, or are they two separate organizations?
David Larson: There’s the Leksell Gamma Knife Society, which just awarded me their Pioneers in Radiosurgery award. They give that award every two years, and I was fortunate to get it in Amsterdam last week. That’s separate from the International Stereotactic Radiosurgery Society, which a few years ago honored me with the Jacob Fabrikant Award of their society. They meet every two years and the Gamma Knife Society meets every two years. At one point the CyberKnife Society was getting started and I was on the board of the CyberKnife Society. I don’t remember exactly what year that was.
Theodore Phillips: Do they still have the Cyberknife Society?
Arjun Sahgal: It’s gone. It’s morphed into the Radiosurgery Society.
David Larson: It’s now called the Radiosurgery Society and they have meetings periodically as well.
Theodore Phillips: They get involved in not only CNS but in the body radiosurgery?
David Larson: The Radiosurgery Society gets involved in brain and body. The ISRS, the International Stereotactic Radiosurgery Society, gets involved in brain and body. The Leksell Gamma Knife Society is mostly brain, though not entirely. These independent societies are exclusively about hypofractionation.
Theodore Phillips: And there’s the Radium Society.
Arjun Sahgal: The Radium Society, I think, is like an ASTRO type of analogue, though physicians other than radiation oncologists can join. I think they also honored you, Dave, with an award a few years ago?
David Larson: Well, they have the annual Janeway Lecture and I delivered the Janeway Lecture a few years ago.
Theodore Phillips: The Radium Society has all kinds of radiotherapy in it and always has had a number of surgeons as members. It’s multi-disciplinary. Arjun, do you have any more questions for Dave along these lines?
Arjun Sahgal: Dave, overall, I think your contributions to the field are immense, especially in the overall move towards eliminating or at least using very sparingly whole brain radiation. I guess if you wanted to look in the future for multiple brain metastasis, perhaps you can share with us what you hope will occur in the next 10 years or 20 years.
David Larson: Well, if you’re asking me to reflect a little bit on future oncology directions, what I would say is that right now we’re just at the starting point of targeted therapy and immunotherapy. I anticipate that there’s going to be great advances made in that area and there will be a great need to know how you should integrate those therapies with radiation in different areas of the body. Whether you have to hold off or continue with radiation, or are there going to be myelosuppressive effects, and so forth. But I think this is a great time for a young faculty member to be involved in radiotherapy, trying to integrate targeted therapy and immunotherapy. This is exciting, and great research opportunities for young faculty, I think. But you mention multiple brain mets. Each year we’re treating more brain mets patients with SRS alone, patients who used to be treated with WBRT alone. That trend will likely continue.
Theodore Phillips: Dave I had a little quick science question for you. I was just at a meeting down at Stanford for Martin Brown’s retirement. An interesting paper was presented as a work in progress. They seem to be getting data now that shows that when you’re doing stereotactic body radiotherapy, the patients are much better if you spaced the fractions rather than giving them on a sequential day. Is that your impression from what you’ve done?
David Larson: I think that makes all the sense in the world. I know of a non-UCSF protocol a few years ago where they were doing three SRS fractions for large brain mets, and they were doing it on successive days. I told them they might be much better off if they treated once a week or so to allow for Reoxygenation and inter-fraction tumor shrinkage. In fact some Japanese data support the idea of three SRS fractions over four weeks, showing that you do great with local control of large brain mets if you deliver 10 Gy, then wait two weeks and give another 10 Gy, and then wait two weeks and give another 10 Gy. Often with successive fractions new plans must be developed as the target volume shrinks. And that’s good. So a pretty good therapeutic ratio in my experience.
Anyway, if I look into my crystal ball I think eventually we’ll more frequently deliver multifraction SRS, both for smaller but especially for larger tumors. Since larger tumors often have significant hypoxia, we should allow more than one day between fractions, maybe up to a week or two between them.
Arjun Sahgal: Do you think that in the future, there’ll be no more 1.8 to 2 Gy fractionation schemes and six to seven weeks of radiation and we’ll all protract?
David Larson: Well, there’s an awful lot of stuff we do that involves large tumors and large amounts of normal tissue. I mean, just think of irradiating head and neck, for example, where you treat a fair amount of normal tissue. So if you’re in a situation where there’s a lot of normal tissue, you’re going to be pretty much stuck with standard fractions. Wishfully thinking, if future targeted therapy or immunotherapy is effective perhaps the total radiation dose can be decreased.
Theodore Phillips: Well, David, let’s get into your personal life a little bit. I understand you just retired from UCSF. What’s your cushy retirement style going to be?
David Larson: Well, I’m still working one or two days a week in Fremont doing radiosurgery. If I’m not doing that, then I’m seeing my kids, or I’m gardening, or I’m skiing or hiking, going to restaurants. I love going to restaurants, and I do that pretty seriously. I do a fair amount of traveling. In fact, I was in Montana not so long ago ago, skiing with some friends from Los Angeles, one of whom I’d treated with SRS for meningioma many years ago. And last night I was channel surfing on TV and I saw the Los Angeles Dodgers playing the San Francisco Giants. There were my two hosts from Montana sitting in the front row behind home plate. I texted them. I said, hey, you’re at the ball game, and they said, hey, my latest followup imaging still looks great!
Theodore Phillips: So your favorite sport, as I knew it, I guess it’s skiing. Is that still the case?
David Larson: Yeah, I love skiing and enjoy it immensely. But I also go to the beach and go running pretty frequently. In fact, today I have an SRS case in Fremont, but before I go I’m going to go to the beach and do a quick run.
Theodore Phillips: Where do you run in San Francisco?
David Larson: I like to run in all sorts of different places, but today I’m going to go run on Ocean Beach.
Theodore Phillips: On Ocean Beach. Okay, great. Can you tell us something about your family?
David Larson: I have three kids, all independent and living in San Francisco. The oldest is 40. He’s a businessman and doing quite well, and he has two kids. So I have two grandchildren. I have a son who’s almost 32, and he’s an attorney in San Francisco. He’s married to another attorney. I have a daughter, and she’s an attorney, and she’s single. I’m fortunate that everybody’s close by, and I’m very proud of my children.
Theodore Phillips: Can you give us some reflections on your career, how you went from physics to medicine and then integrated the two? Do you think that was a successful choice looking back?
David Larson: That integration has really been the best of two worlds. For example, you recall I was the PI on a study carried out at the Stanford Synchrotron Radiation Laboratory where we were awarded one month of 24/7 beam time to study how Auger electrons contributed to BUdR cellular radiosensitization. You, Cliff Ling, Mike Schell and Denis Shrieve participated and we had a lot of fun together, rotating for three shifts per day. We irradiated cultured monolayers of Chinese hamster V79 cells in which thymidine was replaced by BUdR, and we irradiated them with monoenergetic x-rays just above or below the 13.475 KeV K-edge of bromine. As you know, Auger electrons from bromine in DNA are radiotoxic high-LET particles that travel only a minute distance from the bromine and are easily created with x-ray energies just above the K-edge, but not below. We were able to show that Auger electrons are only a minor factor in BUdR cellular radiosensitization. To my knowledge the dominant mechanisms for BUdR radiosensitization remains poorly understood.
Nevertheless there are certainly a zillion good radiation oncologists who don’t have a PhD in physics, so of course that’s not at all necessary. But in terms of my own job satisfaction, I loved the stuff I did in physics. I still maintain contacts with some of my colleagues at Cornell, and I enjoyed my physics career a lot. I do think it was courageous of me to give that up and hope that I’d like medicine as well. It turned out I liked medicine very well. If I would’ve spent the rest of my life as a physicist I think I would’ve been generally happy. I know I’ve been generally happy with being a radiation oncologist. I’ve been very fortunate to have had two challenging careers. Of course, my parents had raised me with the notion that I and my brother and sisters could pursue anything we wanted, our choice, and that they would support us in some way. Well, they supported me in terms of my choices, but financially I was on my own after graduation from UC Berkeley and that worked out okay.
Theodore Phillips: Can you give us a little bit of what you think is going to happen to radiation oncology in the future? In ten years, how do you think our process is going to be?
David Larson: Well, I guess we’re going to be able to improve our outcomes as imaging and integration with planning and real time tracking evolve. As I’ve mentioned before, I think targeted therapy and immunotherapy are going to be making great advances over the next ten years, and that’s going to influence whether we give radiation or not and maybe how we give radiation. So those are the things that are going to be happening, and I think that’s going to lead to an enormous number of publications in the radiation oncology literature.
Theodore Phillips: Do you think hypofractionation will be the dominant treatment modality in ten years?
David Larson: I think we’re going to see more and more hypofractionation but I’m not sure whether it’s going to be dominant. There are many sites to target where you need to include some of the surrounding normal tissue. That’s my guess.
Theodore Phillips: What do you think about particle therapy? Do you think there’s going to be a role for carbon or heavier ions or is that really unnecessary with large fractions?
David Larson: Carbon ions and hypofractionated X-rays may well get you past the shoulder, but we need more experience. For some patients it’s likely true that particle therapy is better. That’s probably a minority of patients per year, but I’ll keep an open mind and I’d be happy to be proven wrong. In the meantime we all recognize that technology evolves and that future machines may well offer radiobiology, imaging, and dosimetry advantages, although cost will remain an issue. It will be up to clinicians to demonstrate advantages.
Theodore Phillips: Dave, just two last questions. Do you have any favorite sayings?
David Larson: Residents often laugh because I use the words “goofy” or “screwy” frequently, such as, this dose distribution looks a little bit goofy. They also like the obvious analogue about Senator Joe McCarthy and communism and WBRT practitioners and brain mets: “There’s communists everywhere who need to be eradicated even if we can’t identify them.” That’s sort of the underlying theory of WBRT: “We know brain mets are there even if we don’t see them.”
Theodore Phillips: Is there anything we forgot to ask you that we should get into this interview?
David Larson: It seems to me we covered a lot of stuff. Thanks a lot. I really enjoyed it.