Intraoperative Radiotherapy for Patients - NCBI

Intraoperative Radiotherapy for Patients with Carcinoma of the Pancreas The Howard University Hospital Experience, 1978-1986

WAYNE B. TUCKSON, M.D., ALFRED L. GOLDSON, M.D., EBRAHIM ASHAYERI, M.D., MICHELLE HALYARD-RICHARDSON, M.D., ROBERT L. DEWITTY, M.D., and LASALLE D. LEFFALL, JR., M.D.

During the period from 1978 to 1986, 106 patients were diagnosed with carcinoma of the pancreas; 30 of these patients were excluded from this study. Of the remaining 76 patients, 40 did not receive intraoperative radiotherapy (IORT) and were used as the nonrandomized control group for the 36 patients who did receive IORT after histologic confirmation of carcinoma of the pancreas. The records of 35 patients were available for review. The group receiving IORT ranged in ages from 43 to 89 years (20 males and 15 females). Seventeen patients had distant metastatic disease. The primary was located in the head of the pancreas in 32 and the body in three. No patient in this group had a curative resection. All patients were treated by a combination of biliary and gastric bypass prior to or concurrent with IORT. IORT was begun only after obtaining a histologic diagnosis and prior to the completion of any anastomosis. Necrotizing pancreatitis occurred in the treated group. There was no statistically significant difference in the survival of the nonrandomized control and treated groups.

ARCINOMA of the pancreas is the fifth leading cause of death from cancer in the United States. Several centers are now using intraoperative radiotherapy (IORT) in patients with localized, nonresectable carcinoma of the pancreas to provide a boost dose directly to the tumor in an attempt to increase survival. IORT has been incorporated with several other treatment modalities including chemotherapy, surgical procedures (resection or bypass), external beam radiation therapy, and sensitizers. The safety of such treatment

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has been demonstrated. Except for the results reported from the Massachusetts General Hospital adding misonidazole to IORT and external beam therapy," 2 the median survival of those having received IORT has been 8.8-12 months. The paucity of major complications in Presented at the 100th Anniversary Meeting of the Southern Surgical Association, Hot Springs, Virginia, December 6-9, 1987. Reprint requests: LaSalle D. Leffall, Jr., M.D., Department of Surgery, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, DC 20060. Submitted for publication: December 10, 1987.

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From the Departments of Radiotherapy and Surgery, Howard University Hospital, Washington, DC

recently treated patients coupled with apparent retardation of local disease and demonstrable necrosis of the tumor in the pancreas suggests that this treatment modality has value in some patients. The records of all patients at the authors' institution diagnosed as having carcinoma of the pancreas from 1978 to 1986 were reviewed, The treatment results are reported for those patients who received IORT with bypass procedures alone or in combination with iodine 125 implantation, external beam radiotherapy, chemotherapy, and/or intraoperative hyperthermia.

Materials and Methods From 1978 to 1986, 106 patients were diagnosed as having carcinoma of the pancreas. In 19 patients the diagnosis was made on clinical grounds without histologic confirmation. Eleven had been diagnosed and treated at other medical centers and were admitted to the authors' institution in a moribund condition. These 30 patients were excluded from this study. Of the remaining 76 evaluable patients, 40 did not receive IORT and were used as a nonrandomized control group for the 36 patients who did receive IORT with 35 of the latter records available for review. The control group included 15 patients who were diagnosed but not treated, one patient who had a curative pancreaticoduodenal resection, 20 patients who had gastric and biliary bypass only, three patients who received bypass and external beam therapy, and one patient who received bypass and iodine 125 implantation. Patients in this group did not receive IORT because of the following: (1) inability to confirm the diagnosis on frozen section; (2) inability to isolate the tumor from surrounding structures; (3) bulky distant metastatic disease; (4) death occurring prior to the treatment date; and

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INTRAOPERATIVE RADIOTHERAPY AND CARCINOMA OF THE PANCREAS

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FIG. 1. The Howard University Hospital Intraoperative Radiotherapy suite consists of a standard operating room combined with a Clinac 18 Linear Accelerator, which can deliver electron beams of 6, 9, 12, 15, or 18 meV.

(5) patient refusal. Patients ranged in age from 36 to 92 years (average: 66.9 years) and included 16 males and 24 females. Twenty-six patients reported weight loss ranging from 8 to 65 lb (average: 24 lb). Twenty-one patients had distant metastatic disease on presentation and the primary was in the head in 38 and body and tail in two. The 35 patients receiving IORT ranged in age from 43 to 89 years and included 20 males and 15 females. The duration of symptoms prior to the institution of therapy ranged from 2 weeks to 13 months. Twenty-one patients on presentation reported weight loss that ranged from 15 to 70 lb (average: 31.6 lb). Symptoms and physical findings were similar to those reported in other series. Seventeen patients had distant metastatic disease found at operation with the primary located in the head of the pancreas in 32 and the body in three. Twelve patients with distant metastases were treated during the Phase I toxicity study to determine side effects and complications of IORT.3 No patients treated with IORT had bulky distant metastases. All patients had nonresectable lesions. Preoperative and postoperative enteral and parenteral hyperalimentation was liberally utilized. Patients were administered general anesthesia in a special IORT suite and prepped and draped in the usual manner (Fig. 1).4 Surgery and radiotherapy were initiated and terminated in the suite; patient transportation was not required. To achieve maximal visualization for both exploration and IORT, a bilateral subcostal surgical incision was usually employed. Once the tumor was exposed and staged, a wedge biopsy or preferably a

transduodenal needle biopsy was performed to obtain frozen section confirmation of the diagnosis. No attempts were made for partial or total resection of the primary. The appropriate electron beam energy and specific applicator (collimator) size, which allowed for at least a 1-2 cm margin of normal tissue, were assessed by palpation and direct measurement of the visualized tumor. The normal uninvolved intra-abdominal structures were then retracted from the treatment field while the applicator was placed down over the tumor. The transparent acrylic (Lucite) portion of the applicator, which is in contact with the tumor surface, permits direct viewing of the radiation field through its sides, and at the same time restrains the uninvolved bowel outside of the direct radiation port (Fig. 2). All treatments were given with electron beams with energies of 9, 12, 15, or 18 meV, with 80-90% depth dose distributions of 3, 4, and 5 cm. The rapid and sharp fall-off in depth dose of electrons is attractive for the intraoperative technique because it limits the exit dose to normal structures, such as the spinal cord, which lies posterior to the tumor. Circular treatment cones of 6.0, 7.5, 8.5, and 9.6 cm in diameter were used to treat the pancreatic lesions. These cones were adequate in treating the well-circumscribed lesions of the pancreas; however, given the multicentricity of many pancreatic malignancies, larger cones of probable rectangular shape may be more efficacious when one considers treating the whole pancreas by the intraoperative technique. Step-

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Ann. Surg - June 1988

FIG. 2. These represent special electron beam coflimators for IORT. The outer part is made of aluminum and is attached to the head of the accelerator, the inner part is made of acrylic and can telescope into the outer aluminum part.

wise decremental doses from 3000, 2500, 2000, and 1500 cGy were given in single doses in the Phase I study. The remaining patients received 2500 cGy as a boost dose plus fractionated external beam photons (usually 4000-4500 cGy). The irradiated volumes, which included the pancreas, its regional lymph nodes, and portions of the duodenum, varied from 30 to 180 cm3. During the interval of irradiation all members of the surgical team left the surgical radiotherapeutic suite. The patients' vital signs were monitored remotely via an oscilloscope mounted just above the treatment console control panel. Additional monitoring was achieved indirectly through a mirror system and the television camera mounted on the wall inside the treatment room. Biliary and gastric diverting procedures were performed after completion of the IORT to avoid further operative trauma and irradiation to new anastomoses. After closure of the surgical wound, patients were transTABLE 1. Number of Patients Treated, Presence or Absence ofDistant Metastases, and Survival Rates No. of Patients Metastases* 21 6 5 2 1

13 3 0 1 0

Survival Treatment IORT +

Bypass only

External beam External beam and iodine 125 External beam and chemotherapy External beam and IOHT

* Distant metastases did not alter survival.

(mo) 6.2 8.8 8.2 6.7 22

ported to the surgical intensive care unit for observation. No special radiotherapy precautions were indicated.

Therapy and Results IORT was given in various combinations including (1) bypass only; (2) bypass and external beam therapy; (3) bypass, external beam, and iodine 125 implantation; (4) bypass, chemotherapy, and external beam therapy; and (5) bypass, external beam, and intraoperative hyperthermia (IOHT). These data including survival rates are outlined in Table 1. One patient was a 56-year-old man who received simultaneous IORT (2500 cGy) and IOHT (43-44 C for 40 minutes) with additional postoperative fractionated external beam irradiation (2000 cGy). Postoperatively, the patient complained of persistent midepigastric pain ultimately requiring implantation of a morphine pump. He survived for 22 months with good quality oflife until his last 2 weeks. He died of massive upper gastrointestinal hemorrhage. Results of an autopsy are pending. Only one patient in the series was still alive functioning fairly well but with progressive disease 11 months after treatment with IORT, chemotherapy, and external beam. Fifty seven per cent of patients receiving IORT had significant relief of abdominal pain within 1-2 weeks after treatment. In a nonrandomized cDntrol group of40 patients treated with varying modalities, the survival rate was 5.4 months.

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Metastases Ofthe five aforementioned treatment groups, no liver or other distant metastases were present in the five patients treated with iodine implantation or in the one patient treated with hyperthermia. One of two patients treated with chemotherapy had liver metastases as did three of six treated with external beam and 13 of 21 treated with IORT alone (Table 1). There was no statistically significant difference in survival in patients with or without distant metastases.

Complications During the Phase I study involving 19 patients, there were three perioperative deaths and three late complications. The complications were: (1) massive upper gastrointestinal hemorrhage from erosion into the superior mesenteric artery resulting in the death of a 65-year-old male 6.5 months after IORT; (2) posterior gastric wall ulcer in a 73-year-old patient who expired 3 months after treatment with massive tumor necrosis; and (3) ascending cholangitis and common bile duct stricture in a 52-year-old patient who died 3 months after treatment. All three patients had treatment volumes greater than 100 cm.3 Two patients received 3000 cGy and one received 2000 cGy. The three perioperative deaths in this group were intraoperative cerebrovascular accident, postoperative hemorrhage secondary to needle biopsy injury to vascular structures, and hepatorenal syndrome and aspiration in a patient with poor liver function. Of the remaining 16 patients, two developed necrotizing pancreatitis and pancreatic abscess: a 72-year-old man treated with IORT and external beam therapy who expired 2 months after treatment and a 56-year-old woman treated with IORT and iodine 125 implantation who died 5 months after treatment. Both had open wedge biopsy because transduodenal biopsy was inconclusive. There was no delayed wound healing. Relatively minor complications included two patients with gastritis and seven patients with prolonged gastric atony in whom portions of the stomach and duodenum were included in the radiation field. Autopsies obtained on eight patients revealed massive tumor necrosis, mild fibrosis, and islands of viable cancer. Discussion There has been continuing interest in the role of IORT for pancreatic cancer since Abe and Takahasi introduced this modality in 1964.5 Howard University Hospital in 1976 was the first institution in the United States to use IORT and began its Phase I study for carcinoma of the pancreas in 1978. The most recent report from Abe et al. suggested that IORT in combination with external beam radiotherapy may improve survival

651 in pancreatic cancer.6 They reported the results of 110 patients with locally advanced disease who were entered into the pilot study.6 Forty-nine patients were treated by

IORT alone (Group 1), 20 patients were treated by IORT followed by external beam radiotherapy (Group 2), and 41 patients were treated by operation alone (Group 3). The IORT dose for patients treated by IORT without external beam irradiation ranged from 3500 to 5500 rads depending on the residual tumor volume and tumor site. For those who were treated by IORT plus external beam irradiation, the IORT dose was 1000-2500 cGy, whereas external beam radiation started 3-4 weeks after IORT had a dosage ranging from 3500 to 5500 cGy with an average of 4000 cGy. The median survivals were 5.5 months for Group 1, 12.0 months for Group 2, and 5.5 months for Group 3. About 70% of their patients who complained of severe abdominal or back pain experienced relief within a week after IORT while 57% of these patients had relief within 1-2 weeks. Approximately 30% of their patients with pancreatic head cancer who received an IORT dose of more than 2500 cGy experienced diarrhea and/or bloody stool and about 10% developed duodenal ulcers. Other complications included prepyloric obstruction in one patient, death probably secondary to acute pancreatic necrosis in another patient, and two patients with delayed gastrointestinal tract bleeding. The most encouraging results for this difficult clinical problem have been reported by groups using intraoperative radiotherapy as a boost in external beam radiotherapy. The advantages of a combined IORT and external beam treatment are as follows: (1) it is difficult to eliminate a bulky tumor by a single IORT dose; (2) a higher dose can be delivered to tumors by external beam plus IORT boost with less risk of adjacent normal tissue necrosis; and (3) the risk of marginal recurrence may be decreased by external beam irradiation.6'7 The results of early clinical work from Japan, which were partly supported by experimental animal studies suggested there were few long-term complications to retroperitoneal structures from IORT.s The acute and late responses of normal canine tissues to large single doses of electron radiation indicated that the major retroperitoneal blood vessels, which were most frequently and unavoidably irradiated, had a high tolerance, while the hollow viscera and solid organs were more sensitive than retroperitoneal structures. In the abdominal solid organs, doses between 2000 and 3000 cGy, in general, led to moderate inflammation, cellular atrophy, and fibrosis. Partial irradiation of the duodenum with doses of 2000-4500 cGy resulted in duodenal narrowing, but as long as the total circumference was not irradiated or the loop of intestine was nonfunctional, stenosis was minimized. Safe clinical practice based on these studies, however, nearly always requires surgical bypass of the biliary

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or gastrointestinal tract if any portion of these organs receive any IORT dose.8'9 Dobelbower et al.,'0 Shipley et al.," and Syed et al.'2 reported median survival times of 1 1-15 months in patients treated with combination interstitial iodine 125 implant and external irradiation. Rich'3 reported that radiation therapy for 41 patients with unresectable pancreatic cancer resulted in a median survival of7 months. There was no difference in median survival for patients receiving external beam alone, IORT plus external beam, or gold 198 implant with or without external beam irradiation.'3 Wood et al. reported 12 patients treated with external photon beam and intraoperative electron beam irradiation who had a median survival of 15 months or more.'4 This survival rate is contrasted with 12 months for patients treated with iodine 125 seeds as boost irradiation and less than 10 months for patients with unresectable disease treated by external beam irradiation and chemotherapy by the Gastrointestinal Tumor Study Group. Six of the 12 patients received chemotherapy. The combination oftailored external beam irradiation and intraoperative boost provided an average tumor dose of6225 cGy, which is the biologic equivalent of 8700 cGy of conventionally fractionated radiation therapy. Complications occurred in all three patients who had the distal stomach and pylorus included in the intraoperative irradiation field-gastric outlet obstruction, pancreatic abscess, and suture line leak. Shipley et al.2 reported the results of 29 patients treated by electron beam IORT plus conventional external beam radiation therapy. Adjuvant chemotherapy (FAM-5 fluorouracil, adriamycin, and mitomycin-C) was given to 23 of the 29 patients while the last 13 patients in the series also received intravenous (I.V.) misonidazole, a drug that sensitizes hypoxic cells to radiation. Their median survival was 16.5 months. Studies with misonidazole are continuing, but these investigators believe that the continued use of misonidazole in this setting is not warranted.' Gunderson et al.'5 reported a similar median survival time of 11-12 months for patients treated with IORT plus external beam irradiation or external beam therapy alone. Fifty-two patients were treated with an IORT dose of 1750 cGy (two patients) or 2000 cGy (50 patients) plus 4500-5000 cGy of fractionated external beam irradiation. They have begun a Phase II pilot trial, which combines upper or total abdominal irradiation and infusion of 5-fluorouracil with tumor nodal irradiation plus IORT to evaluate tolerance and the relative incidence of abdominal failures.'6 Because of these laboratory studies and the results with the one patient treated with simultaneous IORT and intraoperative hyperthermia followed by external beam therapy, the authors have begun a study using a

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combination of these modalities."7 This therapeutic approach has not been used previously for nonresectable pancreatic cancer. The rationale for hyperthermia in cancer therapy is based on various biologic effects that have been confirmed in many in vitro and in vivo studies: (1) hyperthermia kills cells exponentially as a function of time and temperature at or above 43 C; (2) hyperthermia selectively kills S-phase and other radioresistant cells, such as hypoxic tumor cells, acidic cells, and nutritionally deprived cells; (3) hyperthermia not only complements but also acts synergistically with ionizing radiation by inhibiting DNA repair by heat shock proteins or by interacting with cellular membrane structures; and (4) hyperthermia interacts synergistically with cytotoxic agents and can overcome some kinds of drug resistance by various mechanisms, e.g., increasing intracellular drug uptake, inhibiting repair mechanisms, and increasing drug activity. Clinical trials using radiation therapy and adjuvant hyperthermia compared with radiation therapy alone have demonstrated an improvement in partial and complete response rates with the addition of hyperthermia. Overall complete response rates for radiation alone are 30-40% compared with 70-80% for the combined modality approach.'8-2' Conclusion Although IORT has been used for over 50 years, there is now renewed enthusiasm especially with the use of electron beam techniques, which have improved the ability to deliver high intraoperative radiation doses safely. The number of patients in this series is too small to render any definite conclusions. Fifty-seven per cent of these patients had significant relief of severe abdominal and back pain. There was no statistically significant difference in survival whether or not patients were treated with IORT. Nevertheless, with the dismal outlook for patients with cancer of the pancreas, further studies with IORT appear warranted.

References 1. Tepper JE, Shipley WU, Warshaw AL, et al. The role of misonidazole combined with intraoperative radiation therapy in the treatment of pancreatic carcinoma. J Clin Oncol 1987; 5:579584. 2. Shipley WU, Wood WC, Tepper JE, et al. Intraoperative electron beam irradiation for patients with unresectable pancreatic carcinoma. Ann Surg 1984; 289-295. 3. Goldson AL, Ashayeri E, Spinoza MK, et al. Single high dose intraoperative electrons for advanced stage pancreatic cancer; Phase I pilot study. Int J Radiat Oncol Biol Phys 1981;

869-874. 4. Ashayeri E, Dallas T, Goldson AL, et al. Anesthesia in intraoperative radiotherapy patients. J Natl Med Assoc 1986; 78:193199. 5. Abe M, Takahasi M. Intraoperative radiotherapy: the Japanese experience. Int J Radiat Oncol Biol Phys 1981; 7:863-868. 6. Abe M, Shibamoto Y, Takahashi M, et al. Intraoperative radiotherapy in carcinoma of the stomach and pancreas. World J Surg 1987; 11:459-464.

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7. Goldson AL. Past, present and prospects of intraoperative radiotherapy (IORT). Semin Oncol 1981; 8:59-64. 8. Rich TA. Intraoperative radiotherapy. Radiother Oncol 1986; 6:207-221. 9. Sindelar WF, Hoekstra H, Restepo C, Kinsella TJ. Pathological tissue changes following intraoperative radiotherapy. Am J Clin Oncol 1986; 9:504-509. 10. Dobelbower RR, Merrick HW, Ohiya RK, Skeet RT. 125I interstitial implant precision high-dose external beam therapy and 5-FU for unresectable adenocarcinoma of pancreas and extrahepatic biliary tree. Cancer 1986; 58:2185-2195. 11. Shipley WU, Nardi GL, Cohen AM, Lang CC. Iodine- 125 implant and external beam, irradiation in patients with localized pancreatic cancer. 1980; 45:709-714. 12. Syed AM, Puthawola AA, Bevlett DL. Interstitial iodine-125 implant in the management of unresectable pancreatic carcinoma. Cancer 1983; 52:808-813. 13. Rich TA. Radiation therapy for pancreatic cancer: eleven year experience at the JCRT. Int J Radiat Oncol Biol Phys 1985; 11:759-763. 14. Wood WC, Shipley WU, Gunderson LL, et al. Intraoperative irradiation for unresectable pancreatic carcinoma. Cancer 1982; 49:1272-1275.

15. Gunderson LL, Martin JJ, Earle JB, et al. Intraoperative and external beam irradiation ± resection: Mayo pilot experience. Mayo Clin Proc 1984; 59:691. 16. Gunderson LL, Martin JK, Kools LK, et al. Intraoperative and external beam irradiation ± 5-FU for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 1987; 13:319-329. 17. Ashayeri E, Halyard M, Goldson AL, et al. The first simultaneous intraoperative hyperthermia and radiotherapy procedure: dog experiment and technique. J Natl Med Assoc 1987; 79:619624. 18. Arcangeli G, Benassi M, Ciridalli A, et al. Radiotherapy and hyperthermia. Cancer 1987; 60:950-956. 19. Dewhirst MW, Sim DA. Estimation of therapeutic gain in clinical trials involving hyperthermia and radiotherapy. Int J Hyperthermia 1986; 2:165-178. 20. Overgaard J. Rationale and problems in the design of clinical studies. In Overgaard J, ed. Hyperthermia Oncology, Vol. 2. London: Taylor & Francis, 1984; 325-338. 21. Perez CA, Meyer JL. Clinical experience with localized hyperthermia and irradiation. In Overgaard J, ed. Hyperthermia Oncology, Vol. 2. London: Taylor & Francis, 1984; 181-198.

DISCUSSION DR. J. SHELTON HORSLEY III (Richmond, Virginia): It is a pleasure to welcome LaSalle Leffall to membership in the Southern Surgical Association and congratulate him on this excellent presentation. We have followed the work that Howard University has done in intraoperative radiation therapy. They have been at the forefront of this very interesting field. We do not have this capacity at the Medical College of Virginia, so we have no personal experience. Dr. Leffall has outlined the pitfalls and very objectively analyzed his results. I am glad he is moving forward in this field, because I think it does have something to offer in selected areas. People with the expertise and facilities to do this should continue with this investigational type of therapeutic approach. I think one of the exciting things about this work is the pain control. As he pointed out, 57% of his patients got pain control within I to 2 weeks. The Japanese experience is some 70%. Pain control is a truly positive result in patients with carcinoma of the pancreas. I also call to your attention that this has been utilized in other areas of the gastrointestinal tract. The Massachusetts General Hospital and the Mayo Clinic have utilized pain control with rectal carcinoma, and their results, utilizing preoperative radiation therapy followed by resection and intraoperative radiation therapy, have actually shown a significant improvement in survival and decrease in local recurrence, as compared to preoperative radiation and surgical resection. I would like to ask Dr. Leffall: Does he think there is a place for intraoperative radiation therapy following pancreatic resection, such as a Whipple operation, for carcinoma of the head of the pancreas? We will follow this work with great interest, and we wish him well.

beyond the medical literature and read every biography written for information of the past, I knew that LaSalle, being the scholar that he is, would have covered the past contributions in this particular area. Dr. Eloesser's work at the San Francisco County Hospital was not published because the results were not very conclusive and because prior publications were known to him. I mention his work to point out the splendid opportunity we have had in 1987 and the preceding years to do with ease things that were so cumbersome a few years ago. Leo Eloesser, his associates, and his residents have told me how laborious it was to try to pick a patient up from the operating table of the old County Hospital and maintain some semblance of sterility, then place the patient on a stretcher, carry the patient out of the operating room and down the hallway to a rickety old elevator in the next hallway, down the elevator to the therapy department, and then reverse the entire procedure. With what ease LaSalle can accomplish all of this in the operating rooms at Howard University! Mr. President, may I make an entirely irrelevant comment? (Actually, it is not entirely irrelevant, since this meeting began with those beautiful audiovisually recorded words of welcome and congratulations from our President and Mrs. Reagan.) A few years ago, when it was necessary for President Reagan to have a colectomy for what appeared to be, from all preoperative studies, a favorable lesion of the cecum it was felt necessary at that time to have a surgical oncological observer on hand. Had I had the right to decide whether this was necessary or not, I would have made the decision that it was not. I knew that the President's operation was in good hands, that it would go as uneventfully as it did; but had I decided that it was necessary to have an oncological specialist standing by, I would have selected from the neighborhood Dr. LaSalle Leffall, and that would have had one very beneficial effect. We wouldn't have seen the same face on television so often. In fact, I am sure we wouldn't have seen a face at all on television, nor would we have heard so many comments, both relevant and irrelevant, about what took place on that historic date, for Dr. Leffall would surely have remained as quietly in the background as did the Chief of Surgery at the Navy Hospital, Dale Oller, who operated on our president so skillfully. It would have perhaps had an adverse effect in that it would have made those who are so antagonistic to everything that happens in the White House even more antagonistic than they were and are, but it might have also had one other bad effect. It might have delayed the current managment of dissemination of medical news about those in our First Family, which is now handled so beautifully by Colonel John Hutton. At the present time, the correspondents are informed nicely but emphatically that they are not welcome at Navy Bethesda Hospital or any other place where the First Family might be treated. Still, they are welcome around the White House, where concise and well prepared

DR. HARRIS B. SHUMACKER (Bethesda, Maryland): It is a great pleasure for me to listen to LaSalle Leffall present this new work. He knows in what high regard I hold him and how much my colleagues and I in Bethesda enjoy his frequent visits to Walter Reed Army Medical Center as the person in charge of grand rounds. The other day when I was trying to straighten out my continually disordered office, I ran across a four-line letter from Ronald Malt of the Massachusetts General addressed to Ian Munro, Editor of the Lancet. It says: "Perhaps the author of your 'Intraoperative Radiotherapy' (10 December 1983) might want to know that between 1937 and 1942, Leo Eloesser of San Francisco . . . started a series of radiation of 300-400 Roentgens through the open mastectomy wound for breast cancer." His reference is to the biography of Leo Eloesser, subtitled "Eulogy for a Free Spirit," which I wrote some years ago now. (I am not trying to sell my biography, but I do recommend it.) While I do not think that in preparing a paper it is necessary to go