By David Hussey, MD, FASTRO
Question: When did you first become interested in medicine?
Dr. Rubin: As a two year old, according to my family historians, I announced I was going to be a doctor and be devoted to medicine. The earliest recollection I have of my childhood is the inspiration of Louis Pasteur’s, upon receiving the Nobel award, words of contributing first to his parents and family, second to his institutions of learning and his colleagues and third, and most important, to make a lasting contribution to all mankind. Growing up in New York City, I was always on the move and on a fast track, graduating high school at 17 years of age on a rapid advance program. I entered New York University on athletic and scholastic scholarships, attended summer sessions graduating at 19 years to enroll in SUNY, Downstate School of Medicine, receiving my MD in 1950, at age 23. I simultaneously enlisted in the US Army at age 17, was injured playing basketball at NYU, Washington Square Team and Campus developing torn cartilage in my left knee, which lead to my discharge from the army at age 18. As a veteran in the Army’s Officer’s A-12 program, I was awarded a GI scholarship that covered my medical school tuition and expenses.
Question: When did you develop an interest in radiology?
Dr. Rubin: My internship at Kings County Hospital was a rotating first year in medicine, surgery, pediatrics, followed by a second year of medicine (William Dock’s service) where I came in contact with radiology, mainly in diagnosis. Deciding to pursue a career in radiology, I was accepted at the University of Michigan, Ann Arbor, with Fred Hodges and John Holt in diagnosis, and Isadore Lampe and Howard Latourette in therapy, in addition to Bill Bierwaltes in nuclear medicine. It was a very exciting time for the radiologic sciences since the WWII discovery of the atomic bomb and the ability to harness radioactive sources, launching supervoltage treatment with tele-radiocobalt and tele-radiocesium as well as the field of nuclear medicine. Scientific and technologic advances dramatically changed radiology during our residency. Radiation biology and radiation physics were introduced, and I was certified in all fields of radiology-diagnosis, therapy and nuclear medicine in 1955 at the age of 28. Lampe was an imposing clinician, insisting on personally checking every patient set-up, maintaining all patients’ records on punch cards. Lampe was my neighbor, as was Malcom Bagshaw, then, a fellow resident. Bob Parker and Ray Ridings were in our year and remarkably, we all specialized in radiation oncology. However, my first love was diagnostic imaging. Question: Had you planned to go into diagnosis when you went to the University of Michigan for your residency?
Dr. Rubin: Yes, I was leaning toward diagnostic radiology. In fact, my first original contribution was on ‘Secretary Sialography’ with an ENT resident, Irving Blatt. Catherizing Stenson’s or Wharton’s Duct is like catheterizing an angel’s urethra. The unique aspect was obtaining both a before and after a stimulus, emptying sialogram. This was exhibited at both American Roentgen Society (ARS) and at RSNA winning awards at both i.e. silver medal at ARS and magna cum laude at RSNA. My second original contribution was the "The Dynamic Classification of Bone Dysplasias," which was awarded the gold medal of ARS and summa cum laude of RSNA. This was published as my first book and was voted as one of the best and most scientific radiology books published and translated into French and Japanese. My change of direction to radiation therapy was more fortuitous than planned. As noted, I enlisted in the A-12 program in college and in medical school when WWII ended. Thus, when the Korean War began, I was required to serve again as a physician. Being certified in all fields of radiology, I was assigned by the Army to Walter Reed, and then reassigned to the Naval Hospital in Bethesda, Maryland, since they had a small nuclear reactor producing radioisotopes. I was a Lieutenant Commander for a month, then reassigned to NIH, at NCI into the Public Health Service as an assistant surgeon, literally across the street.
The assignment to NCI, the first year it opened, proved to be an apocryphal event and a career changer for me. NIH was a unique academic environment with unrestricted funding for clinical investigation and laboratory research. J. Robert Andrews was the radiation program director, and I became the first chief of clinical radiation therapy at that time. It was the world of tomorrow in radiation facilities, with large 2mev accelerators (Donner Laboratory) able to deliver supervoltage beams, both photons and electrons. Patients could sit or stand on a rotating platform and we had the equivalent of electronic portal imaging (Vidicon) which we published as a continuous visual monitoring since patients moved during treatment. Question: How many patients were you treating a day at NCI versus University of Michigan at that time?
Dr. Rubin: At the University of Michigan, we managed about 50 a day; at NCI, small numbers. Each patient was set up by the resident with the therapist. Then Howard Latourette would check the set-up, then Isadore Lampe. A series of daily radiation oncologist checking each patient set up. This is no longer done, and would be unthinkable in today’s department of radiation oncology. My style was to check and exam each patient on all services, one day a week at the University of Rochester. However, this became supplanted by chart rounds and films without patients after I stepped down from the Chair. Question: How about NCI patient load?
Dr. Rubin: At NCI, small numbers of patients, unlike at the University of Michigan. For a patient to be treated, a protocol was required, an entirely new concept. In fact, if a pregnant woman was admitted, delivering twins, we jokingly said “one would be baptized and the other would not, to be a control”. All of our patients were entered into the J. Robert Andrews design and protocol that extrapolated the Strandquist lines to 10,000cGy in 100 days, treated three times a week on alternate days. The late complications were horrendous and peaked my interest in late effects of radiation treatment.
At NCI, we had our own “Patient-In-Service” and beds as radiation oncologists and we rounded with the medical oncologists (Emiel Frei and Freirich). Our conferences were always multidisciplinary. Methotrexate was discovered at the NCI Clinical Center to eradicate gestational trophoblast tumors. Later, Paul Carbone and Vince DeVita at the clinical center gave birth to multi agent chemotherapy MOPP for Hodgkin’s lymphoma. The surgeons were super aggressive advocating massive resections and reconstructions. Clinical trial investigations were the essence of our collective creativity to cure cancer.
Question: When did you develop an interest in therapy?
Dr. Rubin: When I was introduced to laboratory research with unlimited funding. The concept of animal modeling of clinical problems was encouraged and readily made available. Robert Swain and Howard Andrews (in physics) actualized my experimental ideas. I noted that Strontium 90 was a bone seeking radioisotope, where as Sulfur 35 was a cartilage seeking radioisotope entering into chondoitin sulfate polysaccharide ground substance of cartilage. Utilizing fractionated doses of S35 in growing rats, my goal was to eliminate cartilage growth without ablating the bone marrow and killing them. The S35 experiments produced healthy, long lived achondroplastic rats. This launched me into two new directions.
To recapitulate the radioisotope damage, we slit beamed (1mm) segments of the growing long bone (tibia) and produced a series of modeling errors. This then became the basis for my award winning “Dynamic Classification of Bone Dysplasia”. Reasoning each segment of endochondral bone growth controlled one aspect of bone modeling and bone formation, could be due to a single genetic defect that could produce a variety of bone abnormalities that constitute a bone dysplasia syndrome. If you know how different bones in the body grow and shape, then you could predict the abnormal dysplasia. Rather than multiple genetic defects, one genetic defect in bone growth and modeling could produce the dysplastic skeletal syndrome, i.e. “Dynamic Classification of Bone Dysplasia”. I spent months at Harvard’s Children’s Hospital Radiology Film library to obtain films of the bone dysplasias that were illustrated in the book. I was invited to the University of Paris and gave a two hour presentation in French on this subject. Also, Mckusik at Johns Hopkins to study the Amish population honored me by allowing me to present the concept to the medical school.
Question: What led you to utilize radioisotopes to treat malignancies?
Dr. Rubin: At NCI, the access to the laboratory was wonderful and that's one of the important ingredients in my career. I had a laboratory to simulate and model the clinical problem. My interest at that time was treating chondrosarcoma and we used radioactive sulfur for it. It cost about $1000 a millicurie and as it worked out, we needed something like 10-20 millicuries, so to treat one patient, and the bill was going to be 10 to 20 thousand dollars. But I had to develop a protocol first before I could administer S35 to a patient. As stated, S35 needed to selectively ablate all of the growing cartilage in a young animal. In effect, I created an achondroplastic animal. The clinical analogy was the chondrosarcoma in an adult would be the only growing cartilage; therefore the S35 would enter the growing cartilage of the tumor and ablate the growth fraction.
Question: Why did the residents at the University of Michigan with you become interested in radiation therapy?
Dr. Rubin: My fellow residents at the University of Michigan were more motivated to enter radiation oncology. Bob Parker was recruited to Seattle with Sim Cantril, and Mal Bagshaw joined Henry Kaplan at Stanford, and then located in San Francisco before moving to Palo Alto. Ray Ridings joined the faculty at the University of Mississippi, then private practice. My choice was more by serendipity. After my two years at NCI, I wanted a fuller academic university setting with more variety of patients and an opportunity to teach. My marriage occurred during my residency and my family grew quickly. The income level at NCI was more limiting. The University of Rochester offer was to be the tenth faculty member in diagnosis. Because of my training at the University of Michigan, coupled with being the chief of radiation therapy at NCI, I was encouraged to become the chief of the division of radiation therapy and radioisotopes. My intuition was radiation oncology and nuclear medicines were in rapid phase growth. The University of Rochester proposed I design a new department with supervoltage equipment as the first such radiation treatment facility in Rochester, New York. This signaled the end of general radiologists practicing both diagnosis and part-time radiation therapy on kilovoltage (200-400 kv). This phenomenon was to be repeated across the country as more full time radiation oncologists were trained. At age 30, I was appointed as an assistant professor in 1957 and rapidly built the practice, as well as recruiting rotating radiology residents into radiation therapy. Within four years, I became a tenured full professor, a promotion that is unthinkable and unlikely today in the span of three to four years. Within a decade (1974), I became chair of a free standing division after another decade (1984) before radiation oncology became a full fledged independent department at the University of Rochester created one of the first NCI designated cancer centers that would house multiple disciplines and departments. This allowed for a new trans-disciplinary approach to managing cancer patients since we were housed in the same physical space, sharing core activities and common clinics. Follow up of cancer patients was done with two disciplines at the same time, rather than two separate visits, i.e. gyn oncology patients,
Question: Continue when you were at the University of Rochester, how did you develop your interest in radiation pathology?
Dr. Rubin: When I came to the University of Rochester, unbeknownst to me, the Atomic Energy Commission (AEC) sponsored the department of radiation biology and biophysics as the biologic arm of the Manhattan Project (code name for Atomic Bomb). For my first decade, it was highly classified. Then access to radiation biology research opened in the 1960’s, and led to my teaming up with George Casarett and many other outstanding scientists and investigators: Bill Bales and Irving Spar (Radiolabeled antibodies) Aser Rothstein and Bill Newman (cell membranes and intracellular processes) to name a few. Most of the radiation biologists (Bob Sutherland and Bill Dewey of UCSF) in the country were trained and educated at the University of Rochester.
George Casarett and I became collaborators and as you know, wrote the historic classic “Clinical Radiation Pathology” building on his paradigm that radiation induces a life long biocontinuum of cell and tissue events, changes in the microcirculation, eventual parenchymal cell loss and tissue atrophy leading to premature senescence. My paradigm shift was translating the biocontinuum into clinical events and consequences post radiation. The late effects of radiation in normal tissues have been my major research interest. Fortunately, because of Henry Kaplan’s insights and interests, the concept of being an academic department meant training full time radiation oncologists and pursuing laboratory research; both of these resulted in being awarded and receiving NCI education grants and research grants. This financial support allowed for logarithmic growth and for independent departments of radiation oncology in universities. These P-01 program project grants emphasized translational research, i.e. CERRIS-Clinical Experimental Radiation Research Interactive Sciences. Fortunately, the combination of R01s and P01s allowed me and my radiobiology colleagues (Bob Sutherland, Dietmar Siemann, Peter Keng, and Jackie Williams) to pursue bench research for 40 years at the University of Rochester, until I stepped down from the chair in 1997, at 70 years of age. Question: How did you decide to publish the orange book: “Clinical Oncology for Medical Students and Physicians, a Multidisciplinary Approach”? Was this based on notes that you were passing out to your own medical students?
Dr. Rubin: One of my earliest assignments was accepting an invitation by the University of Rochester to teach medical students about cancer. This began as a lecture series in oncology for third year students, perhaps ten hours, once a week, for a semester, and then designed a three hour examination, asking straight forward questions: detecting, diagnosing, and treating common malignancies, i.e. Lump in breast, cancer in cervix, prostate nodule, etc. This outraged the medical students since it was as long as the examination in medicine and surgery. In time, I created a syllabus on “clinical oncology for medical students” which was published by UR Press and distributed to the entire class (third and fourth year) in 1963 and 1965. Then 1967, the title change to “Clinical Oncology for Medical Students: A multidisciplinary approach”, and in 1974 I added “Physicians aiming at general medical practitioners”. The authorship broadened to involve all major departments in the medical school. An interdepartmental editorial board was appointed which contributed to help create a multidisciplinary spirit in our clinical tumor board conferences. In 1974, 1978 and 1983, “Clinical Oncology, a Multidisciplinary Approach” was adopted by the American Cancer Society (ACS), and enjoyed production runs of 100,000 copies. These were distributed by ACS as a ‘freebee’ and translated into Spanish. This was distributed to all the medical students in the US, North and South America by ACS. I received an award from the USSR Russian Radiologic Society by a professor Pavlov, who honored me because he taught his medical students clinical oncology for decades based on the orange book (often priced at $5-$10).
My commitment to education grew because of the University of Rochester Medical School emphasis on teaching. I was influenced because I was active on the Executive Committee for Education, and my close relationship with John Hansen, who became the dean for education. In the 70’s, a department of medical education was established to which Sharon Krackov (my editorial assistant for the orange book) joined Bill Preston, and directed the medical school education unit. In time, the unit was dissolved and Bill Preston joined our DRO. We embarked on creating “Self Evaluation Modules”, first for medical student courses, which then evolved into “Continuing Medical Education” for CME credits for recertification by ACR and ACRO.
Question: The origin of ASTRO and your role and vision of its beginning?
- “Moments of Decision” was a series of eleven self evaluation module texts published by the American College of Radiology from 1971-1980. The series consisted of recognized radiation oncology leaders in their field of expertise with units on lung cancer, cancer of the eye, cancer of testes, cancer of ovary, cancer of bladder, primary brain tumors, tumors of oral cavity, of the esophagus, of the oropharynx and nasopharynx. Each consisted of approximately 100 patient oriented questions with answers requiring and providing a review of current literature.
- oncoLogic Series, subtitled “Multidisciplinary Decision in Oncology”: This series of modules were again edited by myself, designed by Bill Preston with expert authors. The series was again published by the American College of Radiology from 1981-1984. Again, a large variety of cancers were addressed, perhaps 50 or more volumes.
Dr. Rubin: The NCI, through its support of radiation oncology, education, training, and
research grants provided the stimulus for the academic separation of radiation oncology from diagnostic radiology. A critical component was the NCI-Committee for Radiation Therapy Studies (CRTS), chaired by Gilbert Fletcher and then Simon Kramer with Bill Powers and myself as well as other full time academics. The CRTS was responsible for developing ‘Radiation Research Grand Plans’ every five years, which were translated into R01s and P01s for extramural grants and funding. CRTS also developed “Blue Books” that set the standards for departments of radiation oncology: equipment, staffing, professional and technical numbers, etc. The relationship between major facilities and satellite facilities was to avoid reduplication of expensive equipment in geographic regions. The origin of radiation therapy oncology cooperative group (RTOG) was launched via CRTS. The unique aspect of CRTS is it was an informal committee formed by Palmer Saunders at NCI.
Another critical component was Del Regato’s leadership in forming an “American Club of Radiation Therapists” (ACRT). Juan would buttonhole candidates at the RSNA beginning in 1958 and invite them to lunch or a dinner. The definition of radiation therapist required the exclusive practice of only therapeutic radiology. The club grew steadily from 19 in 1958 to 79 founding members within a few more years. The number of institutions training residents in only radiation therapy kept on increasing so that by 1966, the ACRT became ASTR; the club formalized into a society. The transformation from the duckling stage into a swan occurred when we held out first independent meeting apart from the RSNA at the Biltmore Mountain Shadows Lodge in Arizona with Luther Brady presiding.
Another stimulus was the International Club of Radiation Therapists. As radiation oncology evolved, we recognized in the sixties and seventies, the specialty of radiation therapy originated and was nurtured in Europe. When I was invited to join the International Club of Radiation Therapists, I organized my first sabbatical in 1966 at the Royal Marsden Hospital with luminaries David Smithers, Manny Lederman and Julian Bloom. (In England, I visited Manchester, Edinburgh, Oxford and Cambridge) Then, a decade later at the Institute Gustav Roussy in Paris with Maurice Tubiana, Claude Lalanne, Lucien Isreal and Helen Croizat. In Europe, I visited the Radiumhemmet in Stockholm with Jersey Einhorn, in Belgium Jaques Henri, and in Italy Carlo Nervi.
The mantle of radiation oncology crossed the Atlantic when ASTRO was formed and our membership increased to 50-100 members. It was also driven by major technologic advances and the explosion of science in World War II. Telecobalt and telecesium became available in the 50’s and 60’s then the first linear accelerator was designed by Henry Kaplan and Girston at Stanford University, which led to the Varian corporate headquarters to be in Palo Alto. The new technology and tools of radiation therapy also drove the division of radiology into therapy versus diagnosis. Equally important was the computerization of imaging with cross sectional CT and MRI images completed the split.
Another important step was recruiting full time residents into our specialty. I have trained more than 100 residents in radiation oncology. Having separate straight radiation oncology training programs was an important initiation phase in the development of our specialty. As you know, I've been very actively involved in the medical school teaching and having contact with medical students. These were the two elements you needed for the emergence of radiation oncology as a specialty. Obviously you need to have a faculty being full-time; and then setting up an academic training program so that you can lure medical students on electives in radiation oncology to recruit them as residents. The first residents who I began training were radiology residents, who were rotating through, who decided to become radiation oncologists (Bob Greenlaw and Jerry Green). At this time, our training programs were formed and funded by NCI research training grants. Also, we were beginning to gain more man-power. When we reached about 600, the American Society of Therapeutic Radiology and Oncology was formed, and diagnostic radiology and radiation therapy separated into distinct training programs and disciplines. After that time, residents were board certified only in radiation oncology or radiologic diagnosis; each a there year training program at first, and now four years.
Question: How did you become involved with the JAMA to create the current concepts in cancer series?
Dr. Rubin: I was invited in 1965 by my tennis partner at the Rochester Tennis Club. He was an editor on the JAMA board and invited me to be a special editor to start a series of articles on “Current Concepts in Cancer”, emphasizing a multidisciplinary approach, a relatively new concept. Cancer management was more like passing a baton in a relay race; first the surgeon would diagnose and resect the cancer, and then refer the patient for radiation therapy, and then when the cancer spread, to the medical oncologist. The view I presented was that we needed to huddle together before the patient was treated; the multidisciplinary approach I have experienced at NCI.
Authors of every discipline were requested to present their viewpoints: surgery, radiation oncology, medicine, pathology, radiology, depending on the cancer…each followed by my editorial comment as to achievements and new directions. The series ran for a decade between 1965-1874 and eventually published as a soft cover book in 1975, collating100 series of articles. The readership of JAMA was able to reach and provide medical practitioners with multiple viewpoints on cancer management. Another resultant accolade was the invitation to give the “Presidential Lecture” of the American Urologic Association, the first by a non-urologist. Question: When did you decide to create a separate journal for radiation oncology (Red Journal)?
Dr. Rubin: By the early 70’s, the time was ripe and right to start our new journal, since new instrumentation both in radiation oncology and diagnostic imaging (CT and MR) induced the separation of our respective fields. My experiences as an editor in JAMA and resultant stipends allowed me create an editorial office, and to hire a full time editorial assistant. A journal devoted to radiation oncology with peer review by radiation oncologists was a logical next step in establishing ourselves as a distinct medical discipline. I invited Luther Brady to co-found the new journal which we entitled an “International” Journal of Radiation Oncology”, rather than American. (There was no coin flipping as rumored). By adding “Physics and Biology”, we emphasized radiation oncology was built on a solid scientific basis. Wiley agreed to start the new journal but it became apparent the number of articles submitted easily exceeded the 750 pages for the first year. Our quandary was not to reject new papers of quality and slow future submissions.
At the time (1974), I was on sabbatical in London, and I asked Peter Alexander to review the articles and he agreed that the articles were too good to reject. Peter was an editor of his own journal with Pergammon Press whose publisher was a maverick, Robert Maxwell, a Member of Parliament and a polymath. I requested unlimited pages and he responded that I needed to obtain advertisers and promise to make this the premier journal in our field. The first year, we produced six issues, and then 12 issues, and eventually up to 18 issues, 2-3 volumes a year, by adding supplement issues allowing proceedings of NCI sponsored special radiation research meetings to be published. Most journals are initiated and owned by a publisher or a society. Our contract, allowed me to be a joint owner (50%) of the journal with Pergammon Press.
I shared Maxwell’s vision of being truly international in a globalization sense, with editors in every major country in the world. The economics of a new start-up journal:
- Library subscriptions are more highly priced; equivalent to 5-10 individual subscribers; the estimate was obtaining 500 national libraries to break even.
- Globalization to increase subscribers and libraries to the thousands and become really profitable.
Another saga was obtaining sponsorship of ASTRO, ESTRO and ISRO. ASTRO initially identified itself with the “Cancer” journal of American Cancer Society, and then jointly sponsored IJROBP. The turning point for ASTRO to accept the IJROBP as its official journal was ten years later. At that time, there was a “palace revolt” by my brothers and colleagues: Sam Hellman, Herman Suit and Jim Cox, who wanted ASTRO to own the Journal similar to ASCO. I reiterated my vision being International, and involving radiation biologists and physicists for it to be successful. Eventually, we all agreed to maintain a broad base; as the IJROBP subscriber base grew, it became an ASTRO asset generating annual income for the society without ASTRO investing funds to support an editorial office. I negotiated with Maxwell that when I stepped down as editor-in-chief, my 50% would go to ASTRO. Elsevier bought Pergammon Press and new negotiations began again.
The IJROBP spawned other national radiation oncology journals. The Europeans were the first to split with Harry Bartelink and Jens Overgaard, (co-editors in chief) establishing the European Journal, also with Elsevier. As my academic career evolved, I was invited to visiting professorships in many different countries: Japan, India, and finally China. I encouraged each country to start radiation oncology journals. As I appointed an international editor to the editorial board, I became an ambassador maintaining contact with CRILA, Central and South America, and then Asia after that. They joined as a sponsor as did the International Society of Radiation Oncology (ISRO) of which I was Secretary General for a number of five-year terms. Our colleagues in England were steadfast supporters of IJROBP as was the American Brachytherapy Society.Question: You have had an international vision, what role did you play in forming ISRO?
Dr. Rubin: The driving force was the IJROBP. ESTRO members were more international in their outreach unlike ASTRO. The International Club of Radiation Therapists again, was European based. As I traveled and responded to invitations in Asia and found editors in different countries to join the IJROBP editorial board, it became apparent that with the introduction of megavoltage in Japan, India, China and Thailand, we needed a third meeting part from ASTRO and ESTRO. Although the ISR had a radiation therapy section similar to the RSNA, it was not attended by radiation oncologists. ISRO was formed with the goal of having a meeting every four years in the far east. The first ISRO meeting was in Kyoto and Abe elected to host it. Norman Bleehen was the first president and Sy Levitt second, and during their terms, I served as secretary general. I was invited to the Japanese Radiology Society to give a keynote oration entitled “The Emerging of Radiation Therapy as a Medical Specialty” (their honorary certificate read “The Emergency of Radiation Therapy as a Medical Specialty”). Although this may have been a Freudian slip, it was indicative of the urge to separate from diagnostic radiology. Question: Fletcher was not keen on exhibits at ASTRO; it was your presidency that introduced posters.
Dr. Rubin: As ASTRO president, I wanted to introduce more exhibits and poster sessions, since many papers could not be presented and rejection decreased the possibility of interactions. As you know, this is a vital part of ASTRO and indeed has become another source of income for ASTRO. I created a special supplement for the ASTRO annual scientific meetings so that abstracts and, especially, posters could be published and referenced. This allowed individuals not in attendance to remain current in the field. Also, even if you attended the annual ASTRO meeting, by virtue of with multiple simultaneous sessions, it became impossible to cover all aspects of the annual meeting. Thus, ASTRO abstracts and posters are published as a supplementary IJROBP volume, allowed for more comprehensive coverage.
Question: How did you become involved with creating a Saint?
Dr. Rubin: There was a time in the early 60’s when we could provide highly experimental therapeutics with only the patient’s consent. We didn’t have any Internal Review Boards (IRBs) for protocols. Radioactive materials as plutonium, other radioisotopes were being administered to learn how such elements were metabolized and excreted. University of Rochester had a unique total body counter for metabolic studies. The assumption that IRBs were established because of chemotherapy and medical oncology due to their large current number of protocols is incorrect. IRB surveillance began because of the growth in radiopharmaceuticals and administration of radioisotopes.
My patient’s name was Joe Audino, a builder of traditional homes. He was diagnosed with non-Hodgkin’s lymphoma (NHL), which was referred to as a reticulum cell sarcoma, and was treated repeatedly by radiation as it originated in the axilla and then involved one lymph node bearing region after another. This was prior to the chemotherapy era and each exacerbation was treated with an involved field, perhaps in 15-20 separate sessions over 2-3 years. Finally, the NHL disseminated to the liver, spleen and bone marrow. Because of massive hepatomegaly, a liver palpable at level of pelvis, I indicated the only possibility of treatment was truly experimental-IV radiogold. He agreed and within 2-3 weeks, his liver and spleen regressed, but his bone marrow was ablated. I hospitalized him because of severe thrombocytopenia and neutropenia, and on rounds, Joe would ask “whether Brother Andre told me what to do”. Remarkably, Joe went into complete remission and was totally disease free and lived for another 15-20 years. He even developed a lung cancer ten years later, which was successfully resected. When he lived five years free of disease, I presented his case history to the Society of Nuclear Medicine in Montreal. In the audience was Father Durand who invited me to Saint Joseph’s Basilica, a vast collective of Catholic Churches (similar to the Vatican in size) to meet and lunch with all the Priests and learned that Brother Andre was the central figure who had a shrine filled with crutches as testimony to his healing skills over the decades. Then, I became the central figure in his beatification to Sainthood; the only Saint in Canada. Three miracles are required to begin the beatification process in the Catholic Church. His first miracle was a nun, whose chronic knee effusions resolved the morning after he died, while she cared for him. The second miracle was a farmer with bilateral inguinal hernias, spontaneously reduced. The third and only bonafide miracle was my patient with disseminated NHL Stage IVB, who became more than a five year survivor after intravenous Au198 Therapy (Henry Kaplan adopted this into his therapeutic protocol in advanced Hodgkin’s disease patients with splenic involvement by following splenectomy administering Au198 electively to treat occult liver deposits).
Miracles require a Vatican organized trial to be certified as authentic. Another five years elapsed before the trial was instituted by sending Audino’s original charts and films to Rome- a considerable pile to be stamped with the Papal Seal. Ten priests from St. Joseph’s Basilica came to the University of Rochester and conducted the Trial over three days in my conference room. It began by my initialing all the Papal seals as to their authenticity. The proceedings were recorded by hand by the priests as Audino’s history was dissected and each segment examined. The startling question was “did I think this outcome was a miracle?” I certainly was not going to disparage the trial? Instead, I recalled my background training at the University of Michigan in diagnostic radiology when a diagnosis was questionable on reading a film “A miracle…was a fortuitous concatenation of contiguous circumstances of probable statistical eventuality.” The priests loved the definition and Brother Andre became the first and only Saint to be beatified in Canada. If I had realized God would be on the author line, I would still want to be the first author. Joe Audino built a new home for me and my family and created a beautiful walnut paneled office and furnishings at the University of Rochester. Question: Explain your evolving role of radiation oncology growth at NIH.
Dr. Rubin: As one of the first groups of clinical scientists entering at NIH, I realized the emphasis was on chemotherapeutics. Overtime, serving on different NCI study sections and advisory boards, I realized NCI had become the National Chemotherapy Institute in recasting its mission to find a magic bullet. The model of drug development was adopted as translational research for radiation research. Laboratory modeling in vitro or invivo for efficacy in cancer cells then advancing clinical trials: Phase I Efficacy, Phase II Toxicity to define Tolerance, Phase III compete new agent versus standard therapy, Phase IV Transition into Clinical Practice.
In the early 1980’s, Vince DeVita formed an extramural Board of Scientific Councilors, a multidisciplinary panel of clinical investigators; radiation oncology was represented by Henry Kaplan, Carlos Perez, Sam Hellman and me. Vince assigned me the task of transitioning CRTS into Committee of Radiation Oncology Studies (CROS). The change led to the current structure of the radiation branch as a major program with a permanent office and director at NCI. The plan was my presidential address at ASTRO in 1983. A number of research projects were presented as subsections of radiation oncology program: Hypoxia cell radiosensitizers, Hyperthermia, Combined Chemotherapy and Radiation Therapy, Late Effects and Normal Tissue Tolerance. David Pistema of Stanford University was recruited as the director, then Eli Glatstein. This has gradually evolved into Radiation Oncology Science Program (ROSP), directed by Norman Coleman.
Question: Your involvement in the origin of RTOG/RDOG?
Dr. Rubin: As I mentioned, the CRTS at NCI was the DNA to launch research projects that led to grants in the extramural university settings. Del Regato formed a cooperative group for prostate cancer, then Nickson at Memorial Sloan Kettering launched another group to study Hodgkin’s lymphoma, Simon Kramer formed a group to assess radiation and methotrexate in head and neck cancers. When I proposed studying “carbogen breathing” to combat cancer hypoxia, Gilbert indicated there were too many ongoing groups. Tom Hall became our first cancer center director at the University of Rochester and had just formed the Eastern Oncology Cooperative Group (ECOG); the first national multiprotocol group of chemotherapists. I rewrote the ECOG constitution and bylaws to form the Radiation Therapy Oncology Group’s constitution and bylaws, we then invited 10-20 institutions to become a multiprotocol group. Politically, I anticipated chairing the RTOG, but NCI money became tight and Simon Kramer offered to use his funding to start the new group with his study being the first study. Although assured when Simon Kramer became chair of CRTS, I would become chair of the RTOG. However, I remained vice-chair of RTOG for decades since its operations office was in Philadelphia. I never was elected to chair RTOG.
Both radiologic diagnosis and therapeutic radiology are technologically driven. The computerization of diagnostic imaging preceded the computerization of radiation treatment. Because of CRTS, we launched radiation oncology research plans every five years. The diagnostic radiologists at Vail argued the merits of CT versus MR versus US based on prettier pictures. In a summary statement, I recommended they form a national group akin to RTOG to conduct high quality clinical trials to provide real data instead of better and prettier pictures as to the value and accuracy of different aforementioned procedures. The Radiologic Diagnostic Oncology Group (RDOG) was born when I rewrote the RTOG constitution and it was funded by NCI. The RDOG grew rapidly developing clinical trials to determine the efficacy of new imaging modalities scientifically. David Bragg and Jim Youker developed the first NCI Radiologic Diagnostic Research Plan and morphed RDOG into American College of Radiology Intergroup Network (ACRIN) following our footsteps at NCI and eventually outrunning us in funding. RDOG established themselves at NIH, became the new National Institute of Biomedical Imaging and Bioengineering (NBIB), a pinnacle radiation oncology has not reached at NIH.
Question: Diagnostic Radiology is another side to you and your involvement in Radiologic Diagnostic Oncology Group (RDOG) and American College Radiology Inter Network (ACRIN).
Dr. Rubin: My interest in imaging continued. Although diagnostic radiology divorced from radiation oncology, Radiation oncology has always been entwined with diagnostic imaging as an essential aspect of our practice. The “Oncologic Imaging” textbooks, more than 1000 pages, was co-authored (1st Edition) with David Bragg and Jim Youker and the 2nd edition with David Bragg and Heidi Hrciak, both of whom at different times, chaired diagnostic radiology at Memorial Sloan Kettering. Both volumes were schematized around TNM staging which was a new concept to diagnostic radiologists. These books, as well as RDOG and ACRIN are related to our Creative Concepts Conferences (CCC) in Vail, Colorado traditionally held prior to Christmas. As you know, I was a very active double black diamond skier and discovered Vail on the way to Aspen. Jim Youker and I, while skiing in powder in the backbowls of Vail, dreamed of having our colleagues in this blue sky setting to rap, and spin ideas. Thus, Vail CCC was born. We wanted all the radiologic sciences represented and invited five leaders from diagnosis, five from therapy, five from nuclear medicine, and some from physics and biology. The meeting format was themed around a specific cancer, short presentations (15 minutes), and would start at 6:00 a.m. and end at 9:00 a.m. We would ski and discuss ideas on chairlifts and reconvene at 4:00 p.m. - 6:00 p.m. to have rappateur discussants, no holds barred, meet for cocktails after 6:00 p.m. and dine together. This was repeated for three days. Our gang in radiation therapy consisted of (in addition to myself): Mal Bagshaw, Sam Hellman, Ted Phillips, Len Proznitz, Henry Kaplan, and in diagnosis: Herb Abrams, Dick Greenspan, Eli Zerhouni, Jim Youker, David Bragg, Alex Margulis (also a UM resident), Heidi Hrciak, and in nuclear medicine: Jim Potchen, Alex Gottshalk, and in physics: Bill Hende, and in biology: Bob Kallman, Eric Hall. Keynote speakers were leading edge investigators in different disciplines and specialties. The major corporations in radiation technologic instruments were our sponsors. They would listen to our stream of ideas and on the last session, react to the discussion. Varian Medical Systems, Dick Levy et al added a 2000 club meeting, and for decades, sponsored the radiation oncologists, but we also had GE, Picker, and other diagnostic equipment manufactures. Question: Explain your continuing interest in oncologic imaging and imaging in radiation oncology.
Dr. Rubin: Imaging has always been a vital component in the practice of radiation oncology and increasingly important to tumor targeting in stereotactic techniques of radiosurgery, IMRT and IGRT, installation of dedicated CT units in departments of radiation oncology, even CT/PET and MRI waiting in the wings. The concern is that current radiation oncologists, physicists and dosimetrists are not trained in imaging. Normal tissue imaging is critical because it is often obscured by color wash isodose curves surrounding the GTV and CTV, obscuring normal anatomy detail. The focus is on GTV contours rather than normal tissue content in the wire caging contour displays.
As I noted, I authored and edited “Oncologic Imaging” in two editions with David Bragg, Jim Youker (1994) and Hedi Hriciak (2002) emphasizing the importance of oncologic imaging in a staging work-up prior to therapy. Although many of us favored “oncologic imaging” as a specialty of diagnostic imaging, it has not been able to alter specialization by anatomic region.
Question: How did the University of Rochester play an important role in the use and misuse of radiation therapy for benign disease?
Dr. Rubin: When George Ramsey, our chair of the department of radiology retired, Louis Hemplemann became an interim chair of radiology since our specialty was being divided. Stan Rogoff was chief of diagnosis, while I was chief of therapy; we three rotated executive hospital and medical school committees. Louis Hemplemann had a unique set of qualifications: he was the internist assigned to Los Alamos and became Oppenheimer’s personal physician in the period of building the atomic bomb. When plutonium was discovered, the physicist witnessing the reaction of nuclear fission in a test tube was sprayed when the container exploded and then died in bone marrow failure. This was published in the Journal of Internal Medicine as the first case of radiation lethality due to ingestion of polonium, with no details as to the exact sequence of events as to how the accident occurred.
Louis Hemplemann was fearful of any radiation exposure and became an advocate for banning the use of radiation for benign conditions. His papers and preachings were related to the late induction of cancers following low dose radiation for benign diseases. His apocryphal paper was linking thoracic radiation for so-called “thymus enlargement” in children to avoid a “crib respiratory death” to the later induction of thyroid cancer. By conducting an epidemiologic study carefully following hundreds of patients in Rochester, New York for decades, he uncovered the high association with thyroid cancer in grown children and young adults. He pursued low dose radiation carcinogenesis in patients treated for mastitis, and found a higher incidence of breast cancer compared to controls. The same was true for TB patients who had repeated flouroscopies. Through his research efforts in a large part, our specialty discarded the name of ‘Radiation Therapy’ and changed to ‘Radiation Oncology’, as treatment of benign disease by irradiation was abandoned.
The only remaining bastion for treating benign disease was keloids. In the 90’s, McEvert and Pelligrini, chairs in orthopedics were very active in hip replacements and vexed by heterotopic bone formation (HBF) post operatively. Based on my earlier clinical experimental studies demonstrating radiation impairment of fracture healing, with small doses of radiation, we modeled HBF in chickens and rats. By implanting miniature prosthesis, we demonstrated that small doses- single dose of 8Gy or fractionated to 10Gy was effective without weakening the implant. This dose schedule became standard operating procedure either pre-operatively or post-operatively. Then, my colleagues in vascular surgery requested that I tackle vascular restenosis, post-surgery bypass and post angioplasty in coronaries. Again, modeling in rats post angioplasty of carotid arteries, we demonstrated radiation inhibited restenosis. Much to my amazement, the interventional cardiologists were aggressively modeling in pigs on both sides of the Atlantic favoring endovascular brachytherapy. Eventually, I launched a new journal, entitled the “International Journal of Cardiovascular Radiation Medicine” with Ron Waksman, published by Elsevier. After a decade, drug impregnated stents replaced endovascular brachytherapy and the journal was discontinued. There are many intriguing observations of radiation treatment perturbing normal tissues without invasive techniques that range from TBI and bone marrow transplants to stereotactic radio surgery for cerebral arterio-venous malformations, in the brain and ticdoloreux to mention a few applications. Stan Order and Seigenschmidt each have books compiling radiation treatment in so-called “benign diseases”; since many nonmalignant processes can be very debilitating and life threatening and the risk of inducing cancers is low, there still are indications for treating a few benign entities.Question: New turf in medicine has competition amongst specialties as endovascular brachytherapy and also nuclear medicine with radiolabeled pharmaceuticals. Why did radiation oncologists abandon nuclear medicine?
Dr. Rubin: Radiation oncologists abandoned nuclear medicine because nuclear medicine became a diagnostic specialty focused on imaging. Radioiodine (I131) treatment was mainly indicated and used for benign disease i.e. Thyrotoxicosis rather than thyroid cancer. Phosphorus 32 was used to treat polycythemia and radiogold was abandoned for treating malignant effusions and was replaced by sclerosing solutions. I actually treated rheumatoid arthritis knee effusions with Au198 in approximately 50 patients with direction injection into the joint space with fair results. As radiation oncology increased in size as a department, I was forced to give up nuclear medicine for vaults to house high energy linear accelerators. Nuclear medicine potential has yet to be realized with radiolabeled antibodies for conditions as lymphoma and other oncologic conditions. However, it is unlikely that we will control radiopharmaceuticals as they prove to be more effective in the future.
Question: Amongst your residents and trainees, who have followed an academic career in departments of radiation oncology (DRO) to start up and chair DROs?
- First was Sy Levitt, who chaired a number of DRO’s before settling at the University of Minnesota.
- Then Robert Greenlaw, who was my first full time resident who was recruited to University of Kentucky.
- Chuck Scarantino chaired DRO’s at University of South Alabama (USA), then University of South Carolina and East Carolina.
- Omar Salazar chaired DRO at University of Maryland.
- Henry Keys chaired DRO of Albany Medical School and Hospital.
- Nina Bermudez and Shidnia were on DRO faculty at University of Indiana.
- Gunner Zagars University of Texas MD Anderson Hospital faculty.
- Paul Anthony chairs DRO at University of New Mexico.
- Andre Konski chairs DRO at Wayne Stage University.
- Ray Wynn also on DRO faculty at University of South Alabama.
- Doug Einstein also on DRO faculty at University of Western Reserve, Cleveland
- Larry Marks (my most devoted medical student) chairs DRO University of North Carolina
- Todd Wasserman (medical student) on DRO faculty at Washington University.
Of course, there are a number of faculty at the University of Rochester DRO who were residents and fellows: Alan Katz, Ken Usuki, Hong Zhang, and Deepinder Singh.
We offered Masters and PhD’s in radiobiology with George Casarett, PhD as a mentor.
- Sam Kurahara joined the faculty at the University of Buffalo and long term at the University of Southern California.
- Jack Maier became chair of DRO at Walter Reed Hospital
- Professor M. Fujii in Tokyo was another PhD recipient.
- Paul Van Houtte was the professor and director of radiation oncology at the Jules Bordet Institute, Belgium.
- Castro Vita on the faculty of the University of Buenos Aires Argentina
There were other Europeans whose names escape me at the moment, who came for academic training from Gustav Roussy Institute in Paris, and from the University of Helsinki.
Question: When and how were you honored by establishing an endowed professorship and chair in your name?
Dr. Rubin: It has often been said of me, the only chair in your name will be either on a Ski Lift at Vail or American Airlines. A fateful event occurred early on my arrival to the University of Rochester. A patient named Mayer Mitchell of Mobile, Alabama because they had no advanced radiation treatment facilities. He was referred to me with advanced Hodgkin’s lymphoma (Stage IVB) because Henry Kaplan was traveling and out of the country, and I had published on the Stage IV lymphoma in mice, similar to Hodgkin’s lymphoma in man. We successfully treated him in the early 60s with TNI and MOPP and then was plagued by multiple second malignant neoplasms (breast, skin, bladder prostate) that we managed cure over the decades until his fifth cancer, a rectal cancer, dedifferentiated, metastasized and lead to his demise. Perhaps Mayer’s crowning achievement was my fostering his determination to build a multidisciplinary cancer center at USA melding competitive private practices with the University. First, he established the Philip Rubin Professorship at the University of South Alabama, Mobile in the 70’s. This was amongst the first endowed professorship chairs in radiation oncology. Then, he established a second endowed professorship and chair at the University of Rochester in the 90’s that led to Paul Okunieff becoming the chair at the university. Whenever Stan Order would introduce me at scientific meetings, his salutation was, “Phil is the only radiation oncologist who has two professorships and a sandwich in his name.”
The Mitchell Cancer Center, which just opened in 2009 combines a large clinical facility and adjoined science wing.
Question: What new directions should we be thinking about?
Dr. Rubin: With the world threatened by radiation bioterror and nuclear warfare, radiation oncologists need to be more involved on a national and international level. Developing guidelines for accidental exposure, particularly with increasing nuclear reactors to generate clean electricity on the world stage should be a concern for radiation oncologists. The launching of U-19 bioterror grants has been assigned to the radiation oncology science program at NCI, directed by Norman Coleman. My successor, Paul Okunieff was awarded a grant to pursue early biomarkers and develop radio protectors, much as I did at the University of Rochester. The BEIR reports and UNSEAR should be required reading and radiation oncologists should be playing a larger community role in our respective communities and with Homeland Security issues.
Also, there are two topics I remain most passionate about! First, the importance of the anatomy sciences is as fundamental as physics and biology to our growth. My most recent book is devoted to understanding 3D anatomy emphasizing three planar anatomy displays, common in current treatment planning systems with cross-sectional CTs. Although entitled as “TNM Staging Atlas” by LWW, it was awarded by the British Medical Association (BMA) as the Best Book published in Medicine in the World (2008) competing against thousands of books submitted by all publishers. The reason is the BMA read beyond the misleading title. The book is about 3D oncoanatomy in which “cancer spread patterns” teach a holistic view of anatomy (3 planar). The forth coming 2nd edition will be based on the original elective course for first year medical students and our residents with John Hansen, PhD. John is perhaps the world’s premier anatomist (senior advisory editor for netter volumes). The course was given for two decades to first year medical students. I hope radiation oncologists at other universities will create a first year elective using this volume as a syllabus. One of my few regrets is not advocating oncoanatomy as a medical school elective while I was proactive.
Second, and perhaps more vital and important, is the “Cancer Survivorship”, which is the embodiment of late effects of radiation/chemotherapy. My role in RTOG was fostering and chairing the late effects normal tissue committee, meeting regularly. At five years, we held retreats and in the early 1990’s. The RTOG and EORTC jointly developed the Late Effects Normal Tissue (LENT) Toxicity Scales: subjective, objective, management, analytic criteria (SOMA), and was published on both sides of the Atlantic in IJROBP and EJRO in 1995. Subsequently, in the new millennium, Trotti and I in an NCI sponsored meeting with all disciplines represented, modified the Common Toxicity Criteria of NCI to include late effects with recognition that chemotherapy also produces late effects i.e. CTC V3.0 was published 2002.
Subsequent to my stepping down from the chair of DRO at the University of Rochester, we transformed LENT meetings into Cancer Survivorship Research and Education (CURED). Springer has published our proceedings when meeting annually, often sponsoring and funding meetings personally and through my patient’s generosity. The concept of radiation biocontinuum, the paradigm George Casarett and I introduced in 1968, is being updated by a large group of authors that have become a national infrastructure for CURED. The editors, authors, and I, are dedicated to make this a living document that will lead to Adult Cancer Survivorship Guidelines similar to the Children’s. At the University of Rochester, the Cancer Center has created a Rubin Cancer Survivorship Center and Program, which will be my legacy and hopefully be replicated in departments of radiation oncology nationally and internationally. Lois Travis MD, PhD, is the director and our goal is to create a consortium of dedicated investigators to manage the adverse late effects of cancer treatment (ALERT). The consortium is named ConCured, and this effort has been led by my longest serving faculty member, Sandy Constine, and also Larry Marks.