Lillian Mary Fuller, MD
By Martin Colman, MD, and Moshe Maor, MD
In 2002, ASTRO established the History Committee for the purpose of documenting and recording the history of radiation oncology in the United States. This interview took place at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology in New Orleans on October 7, 2002.
Question: Please state your full name.
Dr. Fuller: Lillian Mary Fuller.
Question: Tell us a little bit about your initial education and how you got into radiation therapy as an introduction.
Dr. Fuller: I was born in Stratford, Ontario, Canada, the home of the Shakespearean Festival, where I attended elementary school and high school. At that time the basic requirement for most Canadian medical schools was a high school education. During those high school years, I was thinking about a career in commercial art. My dad, who was the principal of the high school, said “I will support you in whatever you want to do but do you think you have enough talent to be a commercial artist?” He went on to say that to be successful you not only need to be good, but you need to be exceptionally talented. Then he asked, “Do you think you have enough talent?” When I said I was not sure, he said “let’s explore your other options.” Then we talked about modern languages, and I mentioned being a nurse or a lab technician. He said “No, aim for the top, be a doctor.”
In 1942, when I decided to go to medical school, there were very few women physicians in Canada or the States. However, I did know about Vera Peters, MD, through my mother’s family, who lived in Toronto. Vera was raised in a farming community, where some of my relatives had farms, and she attended elementary school with one of my cousins. My family was very proud of Vera, and they were impressed that, although she was married and had two little girls, she was working full-time in radiation oncology at the Toronto General Hospital. I also knew about Jesse McGeachy, MD, a general surgeon and a friend of my dad’s, who was also at the Toronto General. Both of these women were in fields that were dominated by men at that time. Looking back, I am still amazed that Vera and I were to become close friends and that she would mentor me in the treatment of Hodgkin’s disease.
My becoming interested in radiation oncology is an unusual story. When I was in medical school, I drew cartoons for the medical school page in the Gazette, the university newspaper. I also drew caricatures of students and teachers that were hung on the walls at our medical school parties. Because Ivan Smith, MD, the chief of Radiation Oncology, resembled the actor Edward G. Robinson, I did a sketch of Smith but labeled my drawing “Edward G. Robinson.” The next day, I was summoned to Smith’s office. Needless to say I was very apprehensive, but I need not have been. It turned out that Smith wanted me to put together a brochure on the early detection of cancer for the lay public. When I took sketches for him to look at, he would invite me to see patients with him. At the end of a day of seeing patients, he would review the slides of the new patients, and we would talk about the patients. I was hooked. From then on my goal was to become a radiation oncologist. However, getting started on a residency in radiation oncology was pre-empted by my decision to do six months in pathology and a year in diagnostic radiology because, by being influenced by Smith, I felt I needed a better grounding in both disciplines.
In the early ’50s, there were very few residencies in radiation oncology only. Most were combined with diagnostic radiology with the emphasis on diagnosis. I knew that such residencies were to be avoided. I realized that I needed to find a residency that was scientifically oriented. I found that in the Radiation Oncology Department, directed by Robert Bloor, MD, at the Strong Memorial Hospital in Rochester, NY. These were very heady times. Everyone, the heads of departments, physicists, residents and technicians, were all learning. At Strong, we developed techniques for stabilizing the areas to be treated. We became experts in making casts. We worked with the machine shop to build a back pointer and trunk bridges. We used isodose curves, developed by our physicists, to determine the best fields to achieve optimum tumor doses.
At the same time, we were learning about the malignant diseases themselves, how to treat them and how to care for our patients. We knew very little about the sensitivity of various tumors to irradiation. Nevertheless, young heads of departments thought of themselves as “Young Turks.” Everyone had Ralston Paterson’s textbook “The Treatment of Malignant Disease by Radiotherapy.” It was the Bible.
Question: That is very interesting. What else was going on in the department at that time?
Dr. Fuller: We developed a forerunner of the simulator for checking the accuracy of our treatment fields. We knew from a search of the literature that it was possible to produce acceptable X-ray images using a 220 KV unit by reducing the voltage to 100 KV. Initially, we developed a system for taking X-rays of our fields for cancers of the extremities and the head and neck. This was based on both the areas of the treatment fields and the diameters of the sites under treatment. Subsequently, we modified our techniques to take acceptable films for the chest, abdomen and pelvis. We published “Radiographic Techniques for Use in Radiotherapy” in Kodak’s publication, Radiography and Photography 30: 2-6, 1954.
Question: Was there anything else you were interested in?
Dr. Fuller: Yes. I was interested in giving definitive doses of irradiation to patients with abdominal presentations of the lymhomatous diseases and other sensitive diseases. In most centers, patients were being given palliative doses of irradiation for abdominal presentations. I felt such patients should receive intensive irradiation to the entire abdomen. A satisfactory tumor dose could not be achieved in adults using parallel opposed 220 KV fields. However, it could be achieved using Paterson’s four field trunk bridge technique. Although my original plan was to treat the entire abdomen and pelvis at a rate of 200 roentgens per day, I found that this was poorly tolerated, despite the use of antiemetics, and that the white blood cell and platelet counts fell precipitously. However, by electing to treat the abdomen and pelvis in sequence and by reducing the daily tumor dose to 150 roentgens per day, I was able to deliver a tumor dose of 3,000 roentgens in four weeks in most patients. By shielding the kidneys posteriorly with 2HVL of lead, the dose to these organs was limited to about 2,000 roentgens. During the first few years I was at MD Anderson, I continued to use the trunk bridge on a 220 KV unit to treat abdominal disease because the megavoltage units were needed for patients who required higher doses of irradiation, such as squamous cell cancers of the head and neck.
Question: While you were in Rochester, you were a co-author of a study of neoplasms in individuals who received radiation to the thymus during infancy. Tell us about that.
Dr. Fuller: I unwittingly sewed the seeds for that study after I saw a patient for Bloor, MD, who had been admitted to the hospital with a diagnosis of thyroid carcinoma. She was an attractive teenager. As I was trying to put her at ease talking with her and her parents, I became aware of scars on her neck and lower part of her face. I asked about these and learned that they were the result of plastic surgery for radiation changes in her skin, secondary to treatment she received as an infant for an enlarged thymus. I reported my findings to Dr. Bloor and Hemplemann, MD, the head of our Experimental Radiotherapy department. Dr. Hemplemann felt that we should do a survey of individuals who received irradiation to the thyhmus during infancy to determine if any of them had developed cancer of the thyroid. Conducting this study was a major undertaking, particularly for the pathologist, Lenore Simpson, MD. When the study was completed, we were shocked to learn how many young people had developed thyroid carcinoma. For the most part, the malignancies were low grade, and the patients did well post resection. The incidence of other malignancies was relatively low.
Question: That was a sentinel paper.
Dr. Fuller: Yes it was.
Question: You said you were a fellow at the Memorial Hospital in New York.
Dr. Fuller: Yes, I was at Memorial for about 18 months as a special fellow on the betatron under Jim Nickson, MD. I arrived there in July of 1954.
Question: What was it like being at Memorial at that time?
Dr. Fuller: At that time Memorial was dominated by surgeons. There were no combined clinics. When radiation therapy was felt to be indicated, the surgeons treated their patients with 220 KV irradiation. However, they did not have access to either the cobalt units or the betatron. In order to get enough patients to be treated on the betatron, I spent a lot of time in the surgery clinics and particularly the head and neck clinic. I learned a great deal about the surgical techniques for resecting most solid tumors and about the overall results - both good and bad.
Question: From Memorial you went to Liverpool. Tell us about that.
Dr. Fuller: This too is a complicated story which had to do with the fact that I was a Canadian citizen. As a resident of the States, I could not leave for more than six months without forfeiting the time that had been accumulating towards my being able to apply for citizenship. I had hoped to be able to obtain a fellowship at the Christie Hospital in Manchester. However, their program required 11 months. Subsequently, I was offered a six months fellowship at the Radium Institute in Liverpool, for which I obtained an American Cancer Fellowship. However, my situation was still complicated because I did not want to accept a staff position at Memorial, and I could not afford to leave the country without a job to come back to. I decided to ask Morton Kligerman, MD, for help in finding a job. Mort was one of the Young Turks who had visited the Strong Memorial in Rochester, NY when I was a resident. Mort talked with Gilbert Fletcher, MD. Subsequently, I was interviewed by Dr. Fletcher and by Clark, MD, the President of the MD Anderson Cancer Center. The interview ended with both Fletcher and Dr. Clark appointing me to a senior staff position in the department of Radiotherapy. I was to report to MD Anderson after I completed the fellowship in Liverpool. While I was in England, Fletcher also wanted me to visit the Christie, Royal Marsden and Hammersmith Departments of Radiation Oncology. I was to assess mucosal reactions in patients treated with megavoltage irradiation. Clark agreed that I should visit these centers and gave me a stipend.
Question: Before talking about your career at MD Anderson, would you tell us about your knowledge of the world’s first three cobalt-60 units?
Dr. Fuller: Two of the cobalt-60 sources came from the Chalk River facility in Ontario, Canada. The recipients were Ivan Smith, MD, in London, Ontario and Harold Johns, Ph., in Saskatoon, Saskatchewan. Johns’ unit was installed first, but Smith treated the first patient. Fletcher’s source came from Oak Ridge, Tennessee. It became available in 1953.
Question: I have heard that Fletcher felt he did not get the recognition he should have had and that there was some delay in calibrating the Anderson unit.
Dr.Fuller: I am sorry, I cannot answer these questions because I am not sure of the facts.
Question: Now to return to your story – when did you come to MD Anderson, and what was the Radiation Oncology department like at that time?
Dr. Fuller: When I came to MD Anderson in 1956, the Radiation Oncology department and the machines were loosely organized by disease sites, which resembled the organization of the clinics. Responsibility for one or more disease entities was divided among the different members of the staff. I elected to be in charge of treating Hodgkin’s disease and the other lymphomas. In addition to being responsible for the treatment of specific diseases, we were expected to be able to treat all diseases according to existing protocols. To ensure that we could to do this, Fletcher conducted a mandatory planning clinic every morning. He also rotated us on the machines and the corresponding hospital clinics at three-month intervals. In order for the staff to keep abreast of patients under treatment for disease entities that they were responsible for, each of us conducted a weekly “under treatment” clinic. Also, before a patient started treatment, the radiation oncologist in charge of the disease entity for which the patient was being treated reviewed the treatment films with the staff in charge of the machine. Fletcher was personally involved in the treatment of head and neck, breast and gynecological malignancies.
Question: Was this plan still in force when Fletcher retired?
Dr. Fuller: No. It was modified around 1970 when it became apparent that the staff was becoming overburdened. Fletcher decided that staff responsible for treatment of specific diseases should treat only those diseases and that they should only cover disease-related clinics. Although I had been responsible for the treatment of Hodgkin’s disease and the lymphomas over the years, I had also been responsible for treating children with other malignancies as well as Hodgkin’s disease and lymphomas. However, by 1970, I was only responsible for patients I saw in consultation in the hematology clinic.
Question: Let me be sure I understood – was Fletcher in favor of intensive treatment for Hodgkin’s disease and the other lymphomas at the time you arrived at MD Anderson in 1956?
Dr. Fuller: Yes, he was in favor of intensive treatment for patients with localized disease. When Fletcher arrived at MD Anderson in 1947, most patients in the States were given palliative doses of irradiation that were localized to palpable disease. The philosophy was to retreat when the disease recurred in the irradiated sites. This concept was abhorrent to Fletcher. Like most radiation oncologists, he thought these diseases were generalized from inception. However, he also felt that local control was important to the patient’s quality of life. Consequently, he gave definitive treatment to entire regions. Sometimes he included the adjacent regions prophylactically. Fletcher was encouraged to pursue this course of action by Vera Peters’ paper, published in 1950, in which she demonstrated that Hodgkin’s disease could be cured by irradiation and that cure was related to the stage of disease. When I arrived in 1956, Fletcher was eager to see the results of his approach to treatment.
Question: How did you get started analyzing results?
Dr. Fuller: Despite the fact that patients with stages I and II disease were treated definitively, data pertaining to their disease and treatment had not been coded, so I had to develop a system for coding the case material. Fletcher directed me to the department of Epidemiology for help in doing this. Once the cases were coded, the data was analyzed by hand.’
Question: This must have taken some time.
Dr. Fuller: Yes, it did. However, by 1966, I had published six articles on the treatment of these diseases, including the treatment of abdominal presentations. I also gave the refresher course on the management of these diseases in 1968 and 1969 at the Radiological Society of North America (RSNA).However, despite all the work that was entailed in determining what had been accomplished at MD Anderson, we were stymied.
Question: Why do you say that?
Dr. Fuller: We were stymied for three reasons: our material needed to be reclassified both for Hodgkin’s disease and the non Hodgkin’s lymphomas, we could not predict whether some patients with stage I or II mediastinal presentations of Hodgkin’s disease were more likely to experience spread to the lungs than others and although we were using lymphangiography for staging starting in 1960, we needed an even more precise means for determining the status of the abdomen for patients with negative lymphangiograms.
A gradual breakthrough to solving these problems started with an invitation I received from the Royal Society of Medicine to present the MD Anderson experience in treating Hodgkin’s disease of the mediastinum with irradiation therapy. I immediately contacted Jim Butler, who had recently joined the department of Pathology, and Bao Shan Jing, in diagnostic imaging. The three of us undertook a very comprehensive study of patients with clinical stage I and II Hodgkin’s disease involving the mediastinum. Butler found that almost all the patients had nodular sclerosing disease.
Jing and I reviewed the original and all follow- up films for every patient. I met Jing every Sunday morning for weeks in the reading room of the Radiology department. In those days there was a double row of view boxes on all four walls of the room. During the review process we measured the diameter of the mediastinum at the widest level of the disease. We coded every case for local control and for relapse in the lungs. Most of the patients had been treated definitively with tumor doses of 3,000 rads or more. Local failures were rare among those who received definitive treatment. However, relapse in the lungs was significant among patients whose diameter of the mediastinum, at the level of greatest disease, measured 7.5 cm or more and also among patients who had hilar adenopathy. However, when we compared the incidence of relapse for patients who were treated with a generous mediastinal margin with those who were treated with no margin, including those who were treated with the shrinking field technique, we found no difference in the incidence of pulmonary relapse. Our conclusion from this study was that relapse in the lungs was related to the diameter of the mediastinum at the widest level of the disease and/or to hilar adenopathy. Papers presented at this conference were published in the British Journal of Radiology 40:1967.
Question: Let’s take a break from pathology. Tell us about lymphangiography and staging laparotomy for patients with Hodgkins disease at MD Anderson.
Dr. Fuller; Lymphangiography became available around 1960. At that time physicians in the departments of Hematology and Pediatrics incorporated lymphangiography as a routine procedure in the initial workup of their patients. Jing, MD, elected to personally perform the lymphangiograms. After results of laparotomy as a staging procedure were reported from Stanford, we elected to incorporate laparotomy in our staging armamentarium for patients with upper torso stage I and II presentations, who had negative lymphangiograms. Richard Martin, MD, performed the laparotomies on these patients and Butler, MD, examined and cut the surgical specimens and read the slides. In our opinion, having this team approach made a significant difference in the staging of our patients. The incidence of positive findings at laparotomy was 33percent, whereas the incidence at most institutions, including Stanford, was about 25 percent. Because the incidence of positive abdominal findings at MD Anderson was essentially the same as the incidence of relapse in the abdomen after involved field radiotherapy for patients with upper torso presentations and negative lymphangogams, we elected to treat laparotomy staged I-II patients with upper torso presentations with involved field or mantle radiotherapy only. The exceptions were persons who were committed to a randomized clinical trial. This was contrary to the policy of most oncologists who felt that such patients should receive prophylactic treatment to the paraaortic nodes and spleen as a minimum.
Question: Let’s go back to pathology. Did you do a retrospective study on patients with other presentations of Hodgkin’s disease?
Dr. Fuller: Yes, we did this for all stage I and II presentations according to whether the patients were staged clinically or by lymphangiography or laparotomy. Since most patients with mediastinal presentations had nodular sclerosing disease, we were curious to know what the relative incidence of the four histopathologic subtypes was for other presentations and whether specific pathology affected results.
Question: What did you find?
Dr. Fuller: The incidence of mixed cellularity and nodular sclerosis was about the same for patients with non-mediastinal presentations. The overall five year survival rates for patients with clinical stage I disease, who were treated with involved fields, were equally good for both histopathologic subtypes. However, the results were inferior for patients with clinical stage II mixed cellularity. However, when we looked at the results for lymphangiogram staged patients who were treated with extended fields to both sides of the diaphragm, there was essentially no difference in survival or disease-free survival rates for these two histopathologic subtypes. This was particularly true for patients staged by laparotomy. Actually our disease-free survival results were better for patients with stage I and II non-mediastinal presentations than they were for patients with stage I and II mediastinal disease despite the fact that the patients with non-mediastinal presentations had a proportionately larger number of patients with mixed cellularity disease.
Question: Before we move on, tell us about the results for the Cooperative Clinical Trial and about your involvement with the Southwestern Oncology Group.
Dr. Fuller: With respect to the Cooperative Clinical Trial, I was a member of the Steering Committee headed by Jim Nixon. Other members of the committee were Henry Kaplan, Saul Rosenberg, Vera Peters, Dave Karnofsky, Henry Rappaport and George Hutcheson. I drew and described the treatment fields to be used in the study. These were published as a manual. At that time there was no other comprehensive manual. I also reviewed the radiographic films of the treatment fields for every patient. Finally, because George Hutchison, the statistician for the study, was involved in another project, I did the final analyses and reported on the results of the study at a conference on Hodgkin’s disease chaired by Alexandra Levine, MD.
In my opinion, the results of this study were only meaningful for two groups of patients: those with upper torso disease who were staged by lymphangiography only and were randomized for treatment with involved fields vs. extended fields, which covered the mantle, the paraaortic nodes and the spleen, laparotomy staged patients with upper torso presentations, whose treatment was the same as for the lymphangiogram staged patients. The results for these two groups have been summarized in a table (page 213) in the chapter “Hodgkin’s Disease in Adults: Stages I and II” in our textbook, Hodgkin’s Disease and Non-Hodgkin’s Lymphomas in Adults and Children, by Fuller, Hagemeister, Sullivan and Velasquez. This was published by Raven Press in 1988. Essentially, there was no difference in results for lymphangiogram staged patients who received treatment to both sides of the diaphragm and laparotomy staged patients who were treated with involved fields.
To answer your question about my involvement with the Southwestern Oncology Group, I became involved initially when the pediatric and adult groups were under the same umbrella. I had been invited by the pediatricians to participate in discussions of protocols that included radiotherapy. At that time, I was the only radiation oncologist who was a member of SWOG. Later, radiation oncologists from other institutions joined SWOG. After the pediatric group split from SWOG and were known as POG, I became chairman of the radiotherapy section for both groups. At that time none of the other chemotherapy- oriented oncology groups had radiation therapy representation. However, within a year, radiotherapy was represented in every group.
Question: Let’s talk about the first Combined Modality Study for stage I–II Hodgkin’s disease that was undertaken by SWOG. Who proposed this study? Did this go smoothly?
Dr. Fuller: We developed the idea for this study at MD Anderson. We proposed to randomize laparotomy staged patients with stage I and II Hodgkin’s disease and to treat with involved fieldsand six cycles of MOPP (nitrogen mustard, Oncovin, procarbazine and Prdnisone). However, our proposal was modified by SWOG to compare treatment with extended fields to treatment with involved fields and six MOPP. This study was initiated without the endorsement of the NCI because the chairman, Tom Fry, thought endorsement would be a matter of formality. He was mistaken, and I advised the radiotherapists not to participate in this study unless the conflict was resolved. Although the conflict was eventually resolved, the physicians in the Hematology department at MD Anderson and I decided not to resume entering patients in the SWOG study, and I resigned from SWOG.
However, we did combine our findings for our patients who were treated on the SWOG protocol with our MD Anderson contribution to the Cooperative Clinical Trial of patients who were laparotomy staged and treated with involved vs. extended field radiotherapy that included the mantle, paraaortic region and spleen. The results for this study are shown in tables three and four in the chapter “Hodgkins Disease: Stages I and II in Adults” in our textbook.- The two most important conclusions to be drawn from this study are that for laparotomy staged patients with no mediastinal involvement the disease-free survival results for patients treated with extended fields were no better than those for patients treated with involved fields. However, disease-free results for patients with mediastinal disease greater or equal to 7.5 cm in diameter who were treated with involved fields and six cycles of MOPP were far superior to those of patients treated with only involved or extended fields with or without low dose irradiation to the lungs.
Question: Tell us about the Anderson approach to treating stage III disease. Didn’t that differ rather significantly from treatment at other institutions? Why didn’t you use laparotomy to stage patients with positive lymphangiograms?
Dr. Fuller: Treatment for stage III disease was an evolving process at all major institutions. However, we were the first to treat all patients with stage IIIA and IIIIB disease with curative doses of irradiation. Because I had experience in giving intensive treatment for abdominal presentations of relatively sensitive malignancies at the time I came to Anderson in 1956, I was able to convince the staff of the Hematology department to treat patients with stage IIIA and IIIB to the mantle, abdomen and pelvis with tumor doses of 3,000 rads and to give additional treatment for residual disease. Treatment to the mantle and pelvis were given at a rate of 200 rads tumor dose per day, i.e., 1,000 rads per week. Treatment to the abdomen was given at a rate of 150 rads per day. The liver was included in the treatment fields. Residual disease was boosted by another 1,000 rads. Since this program was initiated before lymphangiography became available, most of these patients had extensive abdominal disease. In initiating treatment, I treated the areas with the most extensive disease first. This allowed me to give a rest interval of about four weeks for the blood counts to recover before starting treatment to the next most critical area. Our five year survival rate for radiation only was about 50 percent.
Our treatment plan was gradually modified as lymphangiography, laparotomy and combination chemotherapy, namely MOPP (nitrogen mustard, Oncovin, procarbazine and prednisone) became available in favor of giving the least amount of treatment compatible with optimal results. This philosophy applied to chemotherapy as well as radiotherapy. For patients with stage IIIA and IIIB disease, treatment was initiated with only two cycles of MOPP. Contrary to the philosophy of some other institutions, where the policy had been to give the same definitive dose of irradiation to all lymph node bearing sites regardless of whether or not there was evidence of disease, our policy was to give a lower prophylactic dose to uninvolved areas. We did not treat the pelvis in laparotomy staged patients whose abdominal disease was confined to the celiac axis and/or spleen. At five and ten years, our freedom from tumor mortality figures for stage IIIA and III B patients was 92 percent and 87 percent respectively, and we had very few complications. Although temporary sterility developed in almost all patients, recovery of ovarian function occurred in a significant number of women who were not treated to the pelvis. Recovery of spermatogenesis occurred in most men, provided the testes were shielded during radiotherapy to the pelvis.
Question: If I remember correctly, you also used a modified mantle technique. What was the reasoning for that?
Dr. Fuller: The reason we did this was based on Fletcher’s view that in treating the mediastinum for known disease, it was not necessary to give a uniform dose to the entire mediastinum. He felt that the area of known disease (usually the upper anterior mediastinum) should receive a maximum dose of 4,000 rads delivered in four weeks and that the remainder should be treated with a prophylactic dose of approximately 3,000 rads. We were able to do this by treating the anterior field with a given dose of 4,000 rads and supplementing the posterior field with sufficient treatment to bring the tumor dose in the upper anterior mediastinum to 4,000 rads. Using cobalt-60, this technique resulted in tumor doses to the posterior mediastinum and mid-plane of the lower mediastinum of about 3,000 and 3500 rads respectively. When we stopped using cobalt-60 in favor of using the six mv Theratron, we inserted blocks to achieve the same dose levels that we had achieved with cobalt-60.
Question: How did this work out?
Dr. Fuller: We had excellent control of the mediastinal disease, and we did not have the spinal cord injuries or the incidence of constrictive pericarditis reported by Stanford.
Question: Let’s leave Hodgkin’s disease and talk about the non-Hodgkins lymphomas. Did you agree with the popular concept that stage I and II presentations of these diseases should be treated with the same fields that were being used for Hodgkin’s Disease?
Dr. Fuller: No. We limited our fields to the presenting areas of disease for both the nodular and the diffuse lymphomas.
Question: What led you to make this decision?
Dr. Fuller: A study of patterns of presentation and initial spread of disease after treatment both for nodular lymphomas and for diffuse large cell lymphomas.
Question: Let’s talk about the nodular lymphomas first.
Dr. Fuller: In our initial experience prior to the development of the lymphangiogram technique and routine bone marrow biopsies, we found that nodular lymphomas involving lymph nodes in the upper torso were almost never presented in the mediastinum, and that spread to the mediastinum or the nasopharynx after involved field radiotherapy to the neck or axilla, which was very rare, whereas relapse in the abdomen was common. Hence we saw no reason to treat patients with upper torso presentations using the mantle. Patients with abdominal presentations accounted for more than half of the patients with clinical stage I-II presentations. These patients usually had extensive abdominal disease and were treated with total abdominal irradiation followed by irradiation to the pelvis.
With the development of sequential staging techniques, we subsequently learned that most patients with a diagnosis of nodular lymphoma have generalized disease on admission. Of those with upper torso presentations, about two-thirds had positive lymphangiograms. Bone marrow biopsy was positive in a few more. Also, about 50 percent of patients with clinical or lymphangiogram stage III disease had involvement of the bone marrow. Our experience with staging laparotomy in lymphangiogram staged I - II patients with upper torso presentations was that two-thirds of those patients had disease in the abdomen. In summary, only about ten of the initial patient population with upper torso presentations had truly localized disease.
The real question is how to treat patients with lymphangiogram stage I-II presentations in the upper torso knowing that two-thirds of them will have occult abdominal disease and knowing that combination chemotherapy has a record of continuously relapsing disease after complete remission. Our current thinking is to initiate treatment for these patients with two to four cycles of combination chemotherapy, such as COP or CHOP – Bleo (cyclophosphamide, adriamycin, oncovin, prednisone and bleomycin), followed by involved field radiotherapy and, finally, complete treatment with chemotherapy. However, patients treated in this fashion must be very closely watched, especially for relapsing disease in the abdomen.
Question: How did you treat stage III disease?
Dr. Fuller: We initiated treatment with four cycles of CHOP – Bleo followed by radiotherapy to the most extensively involved region, which was usually the upper abdomen. After another two cycles of chemotherapy, we irradiated the next area of initial disease, and so on.
Question: What were your results?
Dr. Fuller: Results were related to histopathology. The histopathologic breakdown of 74 stage III patients treated on this program was: small cleaved cell, 38; mixed, 15; large cell, 17. At five years, the survival figures for the three histopathologic subtypes were: 91 percent, 84percent and 40 percent. The freedom from progression of complete responders at five and eight years was identical for mixed and large cell, being 73 percent and 58 percent. They were 65percent and 60percent for small cleaved. Only one relapse occurred 4.5 years after treatment, regardless of the cell type, suggesting that a significant number of patients with stage III disease can be cured with combined modality treatment.
Question: Let’s talk about the diffuse lymphomas and what you think radiotherapy’s role should be in their treatment.
Dr. Fuller: I am going to confine my remarks to the diffuse large cell lymphomas because I think that radiotherapy has a very little role in the management of the other diffuse lymphomas.
Question: Do you think radiotherapy can be used as the sole modality for treating stage I and particularly stage IE presentations of the head and neck?
Dr. Fuller: I know some radiation oncologists think that, after sequential staging, it should be possible to obtain a high cure rate for patients with stage IE disease with radiation only. Except for disease limited to the thyroid, that has not been the experience at MD Anderson. For example, our experience has been that even for patients with very limited disease (T1-T2) of Waldeyer’s ring, the five year survival was about 70 percent. For T3-T4 lesions it was approximately 35 percent. Even 70 percent for favorable disease is not nearly good enough, especially because the salvage rate is very poor for patients with relapsing disease.
Question: Would you treat stage I – II disease with chemotherapy only?
Dr. Fuller: No. Our experience with CHOP – Bleo was that local disease was not totally eliminated in a significant number of patients who were treated with chemotherapy only. We found that the optimum response usually occurred after four cycles of CHOP - Bleo. Consequently, we devised a program consisting of four CHOP-Bleo, radiotherapy to the involved region(s), followed by four CHOP-Bleo. Treatment was completed with four cycles of COP. For patients with disease in the abdomen and the pelvis, we interspersed treatment with four cycles of CHOP-Bleo with radiotherapy. We treated the area with the most extensive disease first. This produced an overall five year survival rate of 85 percent with a disease-free survival rate of 70 percent. However, survival was influenced by a number of independent risk factors.
Question: What did you do for stage III and IV disease?
Dr. Fuller: We rarely used radiotherapy as part of the treatment for stage IV. Our plan for stage III was the same as for stages I and II. The survival rate for these patients was 45 percent at five years and 42 percent at 10 years. However, survival was significantly influenced by prognostic factors and especially tumor burden and LDH level. When we looked at the effect of these factors on survival for our entire population of patients with stage III and stage IV disease who received CHOP- Bleo (stage IV) or CHOP-Bleo and radiotherapy (stage III), we found that results could be correlated with the degree of risk. The most important risk factors were tumor burden and LDH level. Patients with neither of these adverse features had a 10 year survival rate of 88 percent. Those with one risk factor had a 49 percent survival rate, and no patient with both risk factors survived 10 years. Clearly, patients with both risk factors require a different approach to treatment.
Question: Do you have any thoughts about future treatment for the lymphomatous diseases, including Hodgkin’s disease?
Dr. Fuller: Not really. Although we are continually learning about cell and molecular biology, it remains to be seen whether ever increasing information will result in changes in treatment that will produce immediate improvements in results.
Question: Now that you are retired, are you involved in any activities that are related to the medical field?
Dr. Fuller: Yes, I have made a substantial commitment of my time to the Retired Physicians Organization of Harris County, which has about 600 members who are retired physicians. Currently, I am Vice President of the organization and Chairman of the Social Committee. From time to time, I manage to exercise my writing skills by contributing to our monthly newsletter. Occasionally, I draw cartoons for the newsletter, which brings me back to medical school days.
In 2002, ASTRO established the History Committee for the purpose of documenting and recording the history of radiation oncology in the United States. This interview took place at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology in New Orleans on October 7, 2002.
Question: Please state your full name.
Dr. Fuller: Lillian Mary Fuller.
Question: Tell us a little bit about your initial education and how you got into radiation therapy as an introduction.
Dr. Fuller: I was born in Stratford, Ontario, Canada, the home of the Shakespearean Festival, where I attended elementary school and high school. At that time the basic requirement for most Canadian medical schools was a high school education. During those high school years, I was thinking about a career in commercial art. My dad, who was the principal of the high school, said “I will support you in whatever you want to do but do you think you have enough talent to be a commercial artist?” He went on to say that to be successful you not only need to be good, but you need to be exceptionally talented. Then he asked, “Do you think you have enough talent?” When I said I was not sure, he said “let’s explore your other options.” Then we talked about modern languages, and I mentioned being a nurse or a lab technician. He said “No, aim for the top, be a doctor.”
In 1942, when I decided to go to medical school, there were very few women physicians in Canada or the States. However, I did know about Vera Peters, MD, through my mother’s family, who lived in Toronto. Vera was raised in a farming community, where some of my relatives had farms, and she attended elementary school with one of my cousins. My family was very proud of Vera, and they were impressed that, although she was married and had two little girls, she was working full-time in radiation oncology at the Toronto General Hospital. I also knew about Jesse McGeachy, MD, a general surgeon and a friend of my dad’s, who was also at the Toronto General. Both of these women were in fields that were dominated by men at that time. Looking back, I am still amazed that Vera and I were to become close friends and that she would mentor me in the treatment of Hodgkin’s disease.
My becoming interested in radiation oncology is an unusual story. When I was in medical school, I drew cartoons for the medical school page in the Gazette, the university newspaper. I also drew caricatures of students and teachers that were hung on the walls at our medical school parties. Because Ivan Smith, MD, the chief of Radiation Oncology, resembled the actor Edward G. Robinson, I did a sketch of Smith but labeled my drawing “Edward G. Robinson.” The next day, I was summoned to Smith’s office. Needless to say I was very apprehensive, but I need not have been. It turned out that Smith wanted me to put together a brochure on the early detection of cancer for the lay public. When I took sketches for him to look at, he would invite me to see patients with him. At the end of a day of seeing patients, he would review the slides of the new patients, and we would talk about the patients. I was hooked. From then on my goal was to become a radiation oncologist. However, getting started on a residency in radiation oncology was pre-empted by my decision to do six months in pathology and a year in diagnostic radiology because, by being influenced by Smith, I felt I needed a better grounding in both disciplines.
In the early ’50s, there were very few residencies in radiation oncology only. Most were combined with diagnostic radiology with the emphasis on diagnosis. I knew that such residencies were to be avoided. I realized that I needed to find a residency that was scientifically oriented. I found that in the Radiation Oncology Department, directed by Robert Bloor, MD, at the Strong Memorial Hospital in Rochester, NY. These were very heady times. Everyone, the heads of departments, physicists, residents and technicians, were all learning. At Strong, we developed techniques for stabilizing the areas to be treated. We became experts in making casts. We worked with the machine shop to build a back pointer and trunk bridges. We used isodose curves, developed by our physicists, to determine the best fields to achieve optimum tumor doses.
At the same time, we were learning about the malignant diseases themselves, how to treat them and how to care for our patients. We knew very little about the sensitivity of various tumors to irradiation. Nevertheless, young heads of departments thought of themselves as “Young Turks.” Everyone had Ralston Paterson’s textbook “The Treatment of Malignant Disease by Radiotherapy.” It was the Bible.
Question: That is very interesting. What else was going on in the department at that time?
Dr. Fuller: We developed a forerunner of the simulator for checking the accuracy of our treatment fields. We knew from a search of the literature that it was possible to produce acceptable X-ray images using a 220 KV unit by reducing the voltage to 100 KV. Initially, we developed a system for taking X-rays of our fields for cancers of the extremities and the head and neck. This was based on both the areas of the treatment fields and the diameters of the sites under treatment. Subsequently, we modified our techniques to take acceptable films for the chest, abdomen and pelvis. We published “Radiographic Techniques for Use in Radiotherapy” in Kodak’s publication, Radiography and Photography 30: 2-6, 1954.
Question: Was there anything else you were interested in?
Dr. Fuller: Yes. I was interested in giving definitive doses of irradiation to patients with abdominal presentations of the lymhomatous diseases and other sensitive diseases. In most centers, patients were being given palliative doses of irradiation for abdominal presentations. I felt such patients should receive intensive irradiation to the entire abdomen. A satisfactory tumor dose could not be achieved in adults using parallel opposed 220 KV fields. However, it could be achieved using Paterson’s four field trunk bridge technique. Although my original plan was to treat the entire abdomen and pelvis at a rate of 200 roentgens per day, I found that this was poorly tolerated, despite the use of antiemetics, and that the white blood cell and platelet counts fell precipitously. However, by electing to treat the abdomen and pelvis in sequence and by reducing the daily tumor dose to 150 roentgens per day, I was able to deliver a tumor dose of 3,000 roentgens in four weeks in most patients. By shielding the kidneys posteriorly with 2HVL of lead, the dose to these organs was limited to about 2,000 roentgens. During the first few years I was at MD Anderson, I continued to use the trunk bridge on a 220 KV unit to treat abdominal disease because the megavoltage units were needed for patients who required higher doses of irradiation, such as squamous cell cancers of the head and neck.
Question: While you were in Rochester, you were a co-author of a study of neoplasms in individuals who received radiation to the thymus during infancy. Tell us about that.
Dr. Fuller: I unwittingly sewed the seeds for that study after I saw a patient for Bloor, MD, who had been admitted to the hospital with a diagnosis of thyroid carcinoma. She was an attractive teenager. As I was trying to put her at ease talking with her and her parents, I became aware of scars on her neck and lower part of her face. I asked about these and learned that they were the result of plastic surgery for radiation changes in her skin, secondary to treatment she received as an infant for an enlarged thymus. I reported my findings to Dr. Bloor and Hemplemann, MD, the head of our Experimental Radiotherapy department. Dr. Hemplemann felt that we should do a survey of individuals who received irradiation to the thyhmus during infancy to determine if any of them had developed cancer of the thyroid. Conducting this study was a major undertaking, particularly for the pathologist, Lenore Simpson, MD. When the study was completed, we were shocked to learn how many young people had developed thyroid carcinoma. For the most part, the malignancies were low grade, and the patients did well post resection. The incidence of other malignancies was relatively low.
Question: That was a sentinel paper.
Dr. Fuller: Yes it was.
Question: You said you were a fellow at the Memorial Hospital in New York.
Dr. Fuller: Yes, I was at Memorial for about 18 months as a special fellow on the betatron under Jim Nickson, MD. I arrived there in July of 1954.
Question: What was it like being at Memorial at that time?
Dr. Fuller: At that time Memorial was dominated by surgeons. There were no combined clinics. When radiation therapy was felt to be indicated, the surgeons treated their patients with 220 KV irradiation. However, they did not have access to either the cobalt units or the betatron. In order to get enough patients to be treated on the betatron, I spent a lot of time in the surgery clinics and particularly the head and neck clinic. I learned a great deal about the surgical techniques for resecting most solid tumors and about the overall results - both good and bad.
Question: From Memorial you went to Liverpool. Tell us about that.
Dr. Fuller: This too is a complicated story which had to do with the fact that I was a Canadian citizen. As a resident of the States, I could not leave for more than six months without forfeiting the time that had been accumulating towards my being able to apply for citizenship. I had hoped to be able to obtain a fellowship at the Christie Hospital in Manchester. However, their program required 11 months. Subsequently, I was offered a six months fellowship at the Radium Institute in Liverpool, for which I obtained an American Cancer Fellowship. However, my situation was still complicated because I did not want to accept a staff position at Memorial, and I could not afford to leave the country without a job to come back to. I decided to ask Morton Kligerman, MD, for help in finding a job. Mort was one of the Young Turks who had visited the Strong Memorial in Rochester, NY when I was a resident. Mort talked with Gilbert Fletcher, MD. Subsequently, I was interviewed by Dr. Fletcher and by Clark, MD, the President of the MD Anderson Cancer Center. The interview ended with both Fletcher and Dr. Clark appointing me to a senior staff position in the department of Radiotherapy. I was to report to MD Anderson after I completed the fellowship in Liverpool. While I was in England, Fletcher also wanted me to visit the Christie, Royal Marsden and Hammersmith Departments of Radiation Oncology. I was to assess mucosal reactions in patients treated with megavoltage irradiation. Clark agreed that I should visit these centers and gave me a stipend.
Question: Before talking about your career at MD Anderson, would you tell us about your knowledge of the world’s first three cobalt-60 units?
Dr. Fuller: Two of the cobalt-60 sources came from the Chalk River facility in Ontario, Canada. The recipients were Ivan Smith, MD, in London, Ontario and Harold Johns, Ph., in Saskatoon, Saskatchewan. Johns’ unit was installed first, but Smith treated the first patient. Fletcher’s source came from Oak Ridge, Tennessee. It became available in 1953.
Question: I have heard that Fletcher felt he did not get the recognition he should have had and that there was some delay in calibrating the Anderson unit.
Dr.Fuller: I am sorry, I cannot answer these questions because I am not sure of the facts.
Question: Now to return to your story – when did you come to MD Anderson, and what was the Radiation Oncology department like at that time?
Dr. Fuller: When I came to MD Anderson in 1956, the Radiation Oncology department and the machines were loosely organized by disease sites, which resembled the organization of the clinics. Responsibility for one or more disease entities was divided among the different members of the staff. I elected to be in charge of treating Hodgkin’s disease and the other lymphomas. In addition to being responsible for the treatment of specific diseases, we were expected to be able to treat all diseases according to existing protocols. To ensure that we could to do this, Fletcher conducted a mandatory planning clinic every morning. He also rotated us on the machines and the corresponding hospital clinics at three-month intervals. In order for the staff to keep abreast of patients under treatment for disease entities that they were responsible for, each of us conducted a weekly “under treatment” clinic. Also, before a patient started treatment, the radiation oncologist in charge of the disease entity for which the patient was being treated reviewed the treatment films with the staff in charge of the machine. Fletcher was personally involved in the treatment of head and neck, breast and gynecological malignancies.
Question: Was this plan still in force when Fletcher retired?
Dr. Fuller: No. It was modified around 1970 when it became apparent that the staff was becoming overburdened. Fletcher decided that staff responsible for treatment of specific diseases should treat only those diseases and that they should only cover disease-related clinics. Although I had been responsible for the treatment of Hodgkin’s disease and the lymphomas over the years, I had also been responsible for treating children with other malignancies as well as Hodgkin’s disease and lymphomas. However, by 1970, I was only responsible for patients I saw in consultation in the hematology clinic.
Question: Let me be sure I understood – was Fletcher in favor of intensive treatment for Hodgkin’s disease and the other lymphomas at the time you arrived at MD Anderson in 1956?
Dr. Fuller: Yes, he was in favor of intensive treatment for patients with localized disease. When Fletcher arrived at MD Anderson in 1947, most patients in the States were given palliative doses of irradiation that were localized to palpable disease. The philosophy was to retreat when the disease recurred in the irradiated sites. This concept was abhorrent to Fletcher. Like most radiation oncologists, he thought these diseases were generalized from inception. However, he also felt that local control was important to the patient’s quality of life. Consequently, he gave definitive treatment to entire regions. Sometimes he included the adjacent regions prophylactically. Fletcher was encouraged to pursue this course of action by Vera Peters’ paper, published in 1950, in which she demonstrated that Hodgkin’s disease could be cured by irradiation and that cure was related to the stage of disease. When I arrived in 1956, Fletcher was eager to see the results of his approach to treatment.
Question: How did you get started analyzing results?
Dr. Fuller: Despite the fact that patients with stages I and II disease were treated definitively, data pertaining to their disease and treatment had not been coded, so I had to develop a system for coding the case material. Fletcher directed me to the department of Epidemiology for help in doing this. Once the cases were coded, the data was analyzed by hand.’
Question: This must have taken some time.
Dr. Fuller: Yes, it did. However, by 1966, I had published six articles on the treatment of these diseases, including the treatment of abdominal presentations. I also gave the refresher course on the management of these diseases in 1968 and 1969 at the Radiological Society of North America (RSNA).However, despite all the work that was entailed in determining what had been accomplished at MD Anderson, we were stymied.
Question: Why do you say that?
Dr. Fuller: We were stymied for three reasons: our material needed to be reclassified both for Hodgkin’s disease and the non Hodgkin’s lymphomas, we could not predict whether some patients with stage I or II mediastinal presentations of Hodgkin’s disease were more likely to experience spread to the lungs than others and although we were using lymphangiography for staging starting in 1960, we needed an even more precise means for determining the status of the abdomen for patients with negative lymphangiograms.
A gradual breakthrough to solving these problems started with an invitation I received from the Royal Society of Medicine to present the MD Anderson experience in treating Hodgkin’s disease of the mediastinum with irradiation therapy. I immediately contacted Jim Butler, who had recently joined the department of Pathology, and Bao Shan Jing, in diagnostic imaging. The three of us undertook a very comprehensive study of patients with clinical stage I and II Hodgkin’s disease involving the mediastinum. Butler found that almost all the patients had nodular sclerosing disease.
Jing and I reviewed the original and all follow- up films for every patient. I met Jing every Sunday morning for weeks in the reading room of the Radiology department. In those days there was a double row of view boxes on all four walls of the room. During the review process we measured the diameter of the mediastinum at the widest level of the disease. We coded every case for local control and for relapse in the lungs. Most of the patients had been treated definitively with tumor doses of 3,000 rads or more. Local failures were rare among those who received definitive treatment. However, relapse in the lungs was significant among patients whose diameter of the mediastinum, at the level of greatest disease, measured 7.5 cm or more and also among patients who had hilar adenopathy. However, when we compared the incidence of relapse for patients who were treated with a generous mediastinal margin with those who were treated with no margin, including those who were treated with the shrinking field technique, we found no difference in the incidence of pulmonary relapse. Our conclusion from this study was that relapse in the lungs was related to the diameter of the mediastinum at the widest level of the disease and/or to hilar adenopathy. Papers presented at this conference were published in the British Journal of Radiology 40:1967.
Question: Let’s take a break from pathology. Tell us about lymphangiography and staging laparotomy for patients with Hodgkins disease at MD Anderson.
Dr. Fuller; Lymphangiography became available around 1960. At that time physicians in the departments of Hematology and Pediatrics incorporated lymphangiography as a routine procedure in the initial workup of their patients. Jing, MD, elected to personally perform the lymphangiograms. After results of laparotomy as a staging procedure were reported from Stanford, we elected to incorporate laparotomy in our staging armamentarium for patients with upper torso stage I and II presentations, who had negative lymphangiograms. Richard Martin, MD, performed the laparotomies on these patients and Butler, MD, examined and cut the surgical specimens and read the slides. In our opinion, having this team approach made a significant difference in the staging of our patients. The incidence of positive findings at laparotomy was 33percent, whereas the incidence at most institutions, including Stanford, was about 25 percent. Because the incidence of positive abdominal findings at MD Anderson was essentially the same as the incidence of relapse in the abdomen after involved field radiotherapy for patients with upper torso presentations and negative lymphangogams, we elected to treat laparotomy staged I-II patients with upper torso presentations with involved field or mantle radiotherapy only. The exceptions were persons who were committed to a randomized clinical trial. This was contrary to the policy of most oncologists who felt that such patients should receive prophylactic treatment to the paraaortic nodes and spleen as a minimum.
Question: Let’s go back to pathology. Did you do a retrospective study on patients with other presentations of Hodgkin’s disease?
Dr. Fuller: Yes, we did this for all stage I and II presentations according to whether the patients were staged clinically or by lymphangiography or laparotomy. Since most patients with mediastinal presentations had nodular sclerosing disease, we were curious to know what the relative incidence of the four histopathologic subtypes was for other presentations and whether specific pathology affected results.
Question: What did you find?
Dr. Fuller: The incidence of mixed cellularity and nodular sclerosis was about the same for patients with non-mediastinal presentations. The overall five year survival rates for patients with clinical stage I disease, who were treated with involved fields, were equally good for both histopathologic subtypes. However, the results were inferior for patients with clinical stage II mixed cellularity. However, when we looked at the results for lymphangiogram staged patients who were treated with extended fields to both sides of the diaphragm, there was essentially no difference in survival or disease-free survival rates for these two histopathologic subtypes. This was particularly true for patients staged by laparotomy. Actually our disease-free survival results were better for patients with stage I and II non-mediastinal presentations than they were for patients with stage I and II mediastinal disease despite the fact that the patients with non-mediastinal presentations had a proportionately larger number of patients with mixed cellularity disease.
Question: Before we move on, tell us about the results for the Cooperative Clinical Trial and about your involvement with the Southwestern Oncology Group.
Dr. Fuller: With respect to the Cooperative Clinical Trial, I was a member of the Steering Committee headed by Jim Nixon. Other members of the committee were Henry Kaplan, Saul Rosenberg, Vera Peters, Dave Karnofsky, Henry Rappaport and George Hutcheson. I drew and described the treatment fields to be used in the study. These were published as a manual. At that time there was no other comprehensive manual. I also reviewed the radiographic films of the treatment fields for every patient. Finally, because George Hutchison, the statistician for the study, was involved in another project, I did the final analyses and reported on the results of the study at a conference on Hodgkin’s disease chaired by Alexandra Levine, MD.
In my opinion, the results of this study were only meaningful for two groups of patients: those with upper torso disease who were staged by lymphangiography only and were randomized for treatment with involved fields vs. extended fields, which covered the mantle, the paraaortic nodes and the spleen, laparotomy staged patients with upper torso presentations, whose treatment was the same as for the lymphangiogram staged patients. The results for these two groups have been summarized in a table (page 213) in the chapter “Hodgkin’s Disease in Adults: Stages I and II” in our textbook, Hodgkin’s Disease and Non-Hodgkin’s Lymphomas in Adults and Children, by Fuller, Hagemeister, Sullivan and Velasquez. This was published by Raven Press in 1988. Essentially, there was no difference in results for lymphangiogram staged patients who received treatment to both sides of the diaphragm and laparotomy staged patients who were treated with involved fields.
To answer your question about my involvement with the Southwestern Oncology Group, I became involved initially when the pediatric and adult groups were under the same umbrella. I had been invited by the pediatricians to participate in discussions of protocols that included radiotherapy. At that time, I was the only radiation oncologist who was a member of SWOG. Later, radiation oncologists from other institutions joined SWOG. After the pediatric group split from SWOG and were known as POG, I became chairman of the radiotherapy section for both groups. At that time none of the other chemotherapy- oriented oncology groups had radiation therapy representation. However, within a year, radiotherapy was represented in every group.
Question: Let’s talk about the first Combined Modality Study for stage I–II Hodgkin’s disease that was undertaken by SWOG. Who proposed this study? Did this go smoothly?
Dr. Fuller: We developed the idea for this study at MD Anderson. We proposed to randomize laparotomy staged patients with stage I and II Hodgkin’s disease and to treat with involved fieldsand six cycles of MOPP (nitrogen mustard, Oncovin, procarbazine and Prdnisone). However, our proposal was modified by SWOG to compare treatment with extended fields to treatment with involved fields and six MOPP. This study was initiated without the endorsement of the NCI because the chairman, Tom Fry, thought endorsement would be a matter of formality. He was mistaken, and I advised the radiotherapists not to participate in this study unless the conflict was resolved. Although the conflict was eventually resolved, the physicians in the Hematology department at MD Anderson and I decided not to resume entering patients in the SWOG study, and I resigned from SWOG.
However, we did combine our findings for our patients who were treated on the SWOG protocol with our MD Anderson contribution to the Cooperative Clinical Trial of patients who were laparotomy staged and treated with involved vs. extended field radiotherapy that included the mantle, paraaortic region and spleen. The results for this study are shown in tables three and four in the chapter “Hodgkins Disease: Stages I and II in Adults” in our textbook.- The two most important conclusions to be drawn from this study are that for laparotomy staged patients with no mediastinal involvement the disease-free survival results for patients treated with extended fields were no better than those for patients treated with involved fields. However, disease-free results for patients with mediastinal disease greater or equal to 7.5 cm in diameter who were treated with involved fields and six cycles of MOPP were far superior to those of patients treated with only involved or extended fields with or without low dose irradiation to the lungs.
Question: Tell us about the Anderson approach to treating stage III disease. Didn’t that differ rather significantly from treatment at other institutions? Why didn’t you use laparotomy to stage patients with positive lymphangiograms?
Dr. Fuller: Treatment for stage III disease was an evolving process at all major institutions. However, we were the first to treat all patients with stage IIIA and IIIIB disease with curative doses of irradiation. Because I had experience in giving intensive treatment for abdominal presentations of relatively sensitive malignancies at the time I came to Anderson in 1956, I was able to convince the staff of the Hematology department to treat patients with stage IIIA and IIIB to the mantle, abdomen and pelvis with tumor doses of 3,000 rads and to give additional treatment for residual disease. Treatment to the mantle and pelvis were given at a rate of 200 rads tumor dose per day, i.e., 1,000 rads per week. Treatment to the abdomen was given at a rate of 150 rads per day. The liver was included in the treatment fields. Residual disease was boosted by another 1,000 rads. Since this program was initiated before lymphangiography became available, most of these patients had extensive abdominal disease. In initiating treatment, I treated the areas with the most extensive disease first. This allowed me to give a rest interval of about four weeks for the blood counts to recover before starting treatment to the next most critical area. Our five year survival rate for radiation only was about 50 percent.
Our treatment plan was gradually modified as lymphangiography, laparotomy and combination chemotherapy, namely MOPP (nitrogen mustard, Oncovin, procarbazine and prednisone) became available in favor of giving the least amount of treatment compatible with optimal results. This philosophy applied to chemotherapy as well as radiotherapy. For patients with stage IIIA and IIIB disease, treatment was initiated with only two cycles of MOPP. Contrary to the philosophy of some other institutions, where the policy had been to give the same definitive dose of irradiation to all lymph node bearing sites regardless of whether or not there was evidence of disease, our policy was to give a lower prophylactic dose to uninvolved areas. We did not treat the pelvis in laparotomy staged patients whose abdominal disease was confined to the celiac axis and/or spleen. At five and ten years, our freedom from tumor mortality figures for stage IIIA and III B patients was 92 percent and 87 percent respectively, and we had very few complications. Although temporary sterility developed in almost all patients, recovery of ovarian function occurred in a significant number of women who were not treated to the pelvis. Recovery of spermatogenesis occurred in most men, provided the testes were shielded during radiotherapy to the pelvis.
Question: If I remember correctly, you also used a modified mantle technique. What was the reasoning for that?
Dr. Fuller: The reason we did this was based on Fletcher’s view that in treating the mediastinum for known disease, it was not necessary to give a uniform dose to the entire mediastinum. He felt that the area of known disease (usually the upper anterior mediastinum) should receive a maximum dose of 4,000 rads delivered in four weeks and that the remainder should be treated with a prophylactic dose of approximately 3,000 rads. We were able to do this by treating the anterior field with a given dose of 4,000 rads and supplementing the posterior field with sufficient treatment to bring the tumor dose in the upper anterior mediastinum to 4,000 rads. Using cobalt-60, this technique resulted in tumor doses to the posterior mediastinum and mid-plane of the lower mediastinum of about 3,000 and 3500 rads respectively. When we stopped using cobalt-60 in favor of using the six mv Theratron, we inserted blocks to achieve the same dose levels that we had achieved with cobalt-60.
Question: How did this work out?
Dr. Fuller: We had excellent control of the mediastinal disease, and we did not have the spinal cord injuries or the incidence of constrictive pericarditis reported by Stanford.
Question: Let’s leave Hodgkin’s disease and talk about the non-Hodgkins lymphomas. Did you agree with the popular concept that stage I and II presentations of these diseases should be treated with the same fields that were being used for Hodgkin’s Disease?
Dr. Fuller: No. We limited our fields to the presenting areas of disease for both the nodular and the diffuse lymphomas.
Question: What led you to make this decision?
Dr. Fuller: A study of patterns of presentation and initial spread of disease after treatment both for nodular lymphomas and for diffuse large cell lymphomas.
Question: Let’s talk about the nodular lymphomas first.
Dr. Fuller: In our initial experience prior to the development of the lymphangiogram technique and routine bone marrow biopsies, we found that nodular lymphomas involving lymph nodes in the upper torso were almost never presented in the mediastinum, and that spread to the mediastinum or the nasopharynx after involved field radiotherapy to the neck or axilla, which was very rare, whereas relapse in the abdomen was common. Hence we saw no reason to treat patients with upper torso presentations using the mantle. Patients with abdominal presentations accounted for more than half of the patients with clinical stage I-II presentations. These patients usually had extensive abdominal disease and were treated with total abdominal irradiation followed by irradiation to the pelvis.
With the development of sequential staging techniques, we subsequently learned that most patients with a diagnosis of nodular lymphoma have generalized disease on admission. Of those with upper torso presentations, about two-thirds had positive lymphangiograms. Bone marrow biopsy was positive in a few more. Also, about 50 percent of patients with clinical or lymphangiogram stage III disease had involvement of the bone marrow. Our experience with staging laparotomy in lymphangiogram staged I - II patients with upper torso presentations was that two-thirds of those patients had disease in the abdomen. In summary, only about ten of the initial patient population with upper torso presentations had truly localized disease.
The real question is how to treat patients with lymphangiogram stage I-II presentations in the upper torso knowing that two-thirds of them will have occult abdominal disease and knowing that combination chemotherapy has a record of continuously relapsing disease after complete remission. Our current thinking is to initiate treatment for these patients with two to four cycles of combination chemotherapy, such as COP or CHOP – Bleo (cyclophosphamide, adriamycin, oncovin, prednisone and bleomycin), followed by involved field radiotherapy and, finally, complete treatment with chemotherapy. However, patients treated in this fashion must be very closely watched, especially for relapsing disease in the abdomen.
Question: How did you treat stage III disease?
Dr. Fuller: We initiated treatment with four cycles of CHOP – Bleo followed by radiotherapy to the most extensively involved region, which was usually the upper abdomen. After another two cycles of chemotherapy, we irradiated the next area of initial disease, and so on.
Question: What were your results?
Dr. Fuller: Results were related to histopathology. The histopathologic breakdown of 74 stage III patients treated on this program was: small cleaved cell, 38; mixed, 15; large cell, 17. At five years, the survival figures for the three histopathologic subtypes were: 91 percent, 84percent and 40 percent. The freedom from progression of complete responders at five and eight years was identical for mixed and large cell, being 73 percent and 58 percent. They were 65percent and 60percent for small cleaved. Only one relapse occurred 4.5 years after treatment, regardless of the cell type, suggesting that a significant number of patients with stage III disease can be cured with combined modality treatment.
Question: Let’s talk about the diffuse lymphomas and what you think radiotherapy’s role should be in their treatment.
Dr. Fuller: I am going to confine my remarks to the diffuse large cell lymphomas because I think that radiotherapy has a very little role in the management of the other diffuse lymphomas.
Question: Do you think radiotherapy can be used as the sole modality for treating stage I and particularly stage IE presentations of the head and neck?
Dr. Fuller: I know some radiation oncologists think that, after sequential staging, it should be possible to obtain a high cure rate for patients with stage IE disease with radiation only. Except for disease limited to the thyroid, that has not been the experience at MD Anderson. For example, our experience has been that even for patients with very limited disease (T1-T2) of Waldeyer’s ring, the five year survival was about 70 percent. For T3-T4 lesions it was approximately 35 percent. Even 70 percent for favorable disease is not nearly good enough, especially because the salvage rate is very poor for patients with relapsing disease.
Question: Would you treat stage I – II disease with chemotherapy only?
Dr. Fuller: No. Our experience with CHOP – Bleo was that local disease was not totally eliminated in a significant number of patients who were treated with chemotherapy only. We found that the optimum response usually occurred after four cycles of CHOP - Bleo. Consequently, we devised a program consisting of four CHOP-Bleo, radiotherapy to the involved region(s), followed by four CHOP-Bleo. Treatment was completed with four cycles of COP. For patients with disease in the abdomen and the pelvis, we interspersed treatment with four cycles of CHOP-Bleo with radiotherapy. We treated the area with the most extensive disease first. This produced an overall five year survival rate of 85 percent with a disease-free survival rate of 70 percent. However, survival was influenced by a number of independent risk factors.
Question: What did you do for stage III and IV disease?
Dr. Fuller: We rarely used radiotherapy as part of the treatment for stage IV. Our plan for stage III was the same as for stages I and II. The survival rate for these patients was 45 percent at five years and 42 percent at 10 years. However, survival was significantly influenced by prognostic factors and especially tumor burden and LDH level. When we looked at the effect of these factors on survival for our entire population of patients with stage III and stage IV disease who received CHOP- Bleo (stage IV) or CHOP-Bleo and radiotherapy (stage III), we found that results could be correlated with the degree of risk. The most important risk factors were tumor burden and LDH level. Patients with neither of these adverse features had a 10 year survival rate of 88 percent. Those with one risk factor had a 49 percent survival rate, and no patient with both risk factors survived 10 years. Clearly, patients with both risk factors require a different approach to treatment.
Question: Do you have any thoughts about future treatment for the lymphomatous diseases, including Hodgkin’s disease?
Dr. Fuller: Not really. Although we are continually learning about cell and molecular biology, it remains to be seen whether ever increasing information will result in changes in treatment that will produce immediate improvements in results.
Question: Now that you are retired, are you involved in any activities that are related to the medical field?
Dr. Fuller: Yes, I have made a substantial commitment of my time to the Retired Physicians Organization of Harris County, which has about 600 members who are retired physicians. Currently, I am Vice President of the organization and Chairman of the Social Committee. From time to time, I manage to exercise my writing skills by contributing to our monthly newsletter. Occasionally, I draw cartoons for the newsletter, which brings me back to medical school days.
