Minutes of First Meeting for Southeast Cooperative Group on Tumor-Localizing Radioindicators, Oak Ridge Associated Universities' Dedical Division (6-18-70)

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Southeast Cooperative Group on Tumor-Localizing Radioindicators Minutes of First Meeting Oak Ridge Associated Universities' Medical Division This meeting was held to consider the possibility of organizing a cooperative group to determine the clinical usefulness of carrier-free 67Ga in the diagnosis and staging of cancer. The work done at Oak Ridge Associated Universities' Medical Division had shown a remarkable localization in a significant share of cancer patients studied. The Division's Advisory Committee, at a Spring 1970 meeting, had suggested that a cooperative study would make it possible to broaden the study to include adequate numbers of patients in various The meeting w a s supported by a special grant of $7,100 provided by the American Cancer Society which had been contacted through the helpfulness of The meeting was set up on rather short notice; it w a s believed that the problem w a s urgent enough to just@ some haste. Invitations were sent to the nuclear medicine departments of the 22 medical schools affiliated with Oak Ridge Associated Universities. Of these, 1 2 sent representatives, two expressed varying degrees of interest but could not send a representative, and eight did not respond to the initial letter. Also invited were Dr. Sidney L. Arje, Vice President for Clinical Research, and Dr. Arthur I. Holleb, Senior Vice President for Medical Affairs, of the American Cancer Society; Dr. Joseph Goldstein, of the Division of Biology and Medicine, U. S. Atomic Energy Commission; and Dr. William Powers, Program Director for Radiation, Clinical Investigations Branch, of the National Cancer Institute. None of these were able to attend but all expressed interest, especially Dr. Powers. (See report of comments by Andrews.) At the suggestion of Dr. Holleb, Dr. John Laughlin w a s invited; he was unable to attend but sent Dr. Helen Woodard. A complete list of attendees is given in Appendix A. The first half of the morning w a s spent on an agenda planned by the Medical Division; the r e s t of the day on an agenda planned at the meeting. The first speaker was G. A . Andrews, Chairman of the Medical Division, who reviewed the reasons for the meeting. Among the questions about E7Ga that need to be answered a r e the following that were listed in the invitation to the

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1. Which groups of malignant neoplasms have the ability to concentrate this nuclide; how uniform is this ability within any one group, and how uniform is it in one patient with multiple lesions? 2. How do patients within any one diagnostic category vary in this concentrating ability, and can these variations be related to histopathology, previous therapy, o r other clinical features ? 3. What a r e the best scanning and measurement conditions for various types, sites, and sizes of lesions? 4. How does 67Ga compare with other radionuclides that concentrate in tumors in soft tissues, such a s compounds of indium, selenium, iodine-labeled antibodies, etc. ? It seems quite likely that with enough carefully correlated clinical experience one might be able to say that for certain groups of malignancies one agent would be preferable, while for others a different one should be used. It would be very desirable to know for the various clinical groups what correlation, if any, exists in the localization of these various 5. Information is needed on the concentration, if any, in inflammatory lesions o r other non-malignant diseases. Additional questions that might be considered are: 6. Can 67Ga serve to locate occult cancers in patients suspected of having an undiagnosed malignancy? 7. Since preliminary data suggest that effective therapy greatly reduces a tumor's ability to concentrate 67Ga, could this agent be used in the early determination of response to treatment, such a s hormone therapy for breast carcinoma. Andrews discussed possible financial support for a collaborative study. The Atomic Energy Commission would be very interested in this work but it seems unlikely that it could support much beyond the existing work at Oak Ridge Associated Universities. The American Cancer Society very graciously and readily supported the present preliminary meeting. In a letter from Dr. Holleb, we were informed that they would be glad to consider a proposal for the expanded study, but that their funds were very limited, The most encouragement had come from Dr. William Powers, whom Andrews had interviewed the previous week. He mentioned that the National Cancer Institute is already supporting collaborative projects in diagnostic radiology and in therapeutic radiology but not in nuclear medicine. On the other hand, he emphasized that other cooperative groups had

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learned of various pitfalls and how to deal with them, and that the review committee would not approve a proposal that did not show excellent planning and adequate consideration of methods of obtaining and dealing with quantitative data. A proposal with more than one protocol appears preferable. If we wish to prepare a proposal, Dr. Powers is willing to work actively to help u s do so. Such a proposal would need to be submitted one month earlier than the usual NIH deadlines, to allow for dealing with the multiple-institution Dr. Richard King had commented in a letter to Andrews that the American College of Radiology had in the past been of service as a data-collecting agency for cooperative studies and might be called on to help with this one. Dr. C. Lowell Edwards reported on the clinical experience with 67Ga in approximately 100 patients who received up to 70 microcuries per kg. These patients had known malignant tumors of a variety of histologic types but lymphomas comprised the largest number. Best results were in patients with reticulum- cell sarcoma and lymphoblastic lymphoma, all of whom nad positive scans. Positive scans were obtained in 15 of 22 patients with Hodgkin’s disease. Tumor localization was seen in a number of patients with carcinoma of the lung and poorly differentiated adenocarcinoma of different sites. Tumor concentrations of up to 60% of the injected dose per kilogram of tumor tissue was observed in tissue recovered by biopsy o r autopsy. Assay of other tissues and organs obtained at autopsy show a wide variation of concentration in some tissues. Besides tumor, other tissues that showed concentration of the nuclide were the bone marrow, liver, and spleen. Dr. R. L. Hayes briefly covered the animal studies that have been carried out at ORAU Medical Division. Thirteen different tumor types in the mouse, rat, and hamster have shown variable but distinct affinities for gallium. The highest G7Ga concentration in tumor was observed in a rat hepatoma (10.0% administered dose per gram of tumor, 14 times that of liver and 110 times that of muscle). Viable tumor generally shows a 67Ga concentration approximately four times that of necrotic tumor tissue. By 24 hours, tumor concentration is maximum and remains essentially constant through six days. In initial studies in humans, an arbitrary citrate dose level of 7 mg/kg was used. Subsequent studies in animals showed that citrate is not required for other than convenience in pH adjustment and a s an assurance against the possibility of colloid formation during dose preparation. Administration of stable gallium with G7Ga produces a greatly decreased concentration in tumor tissue. Dr. Larry Brown, of the Isotopes Division of Oak Ridge National Laboratory, spoke about the preparation and cost of 67Ga. It is made inthe ORNL 86-inch cyclotron by a p, 2n interaction with 68Zn. At present it is supplied for $10 per millicurie, plus handling and shipping; this is an artificial cost awlicable to an experimental product. A t some point in the future it will need to be sold at full

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cost recovery. Irradiation cost would depend upon batch size. F o r example, some very tentative estimates a r e as follows: Cost per millicurie $13.8 $9.8 $7.9 $5.9 This would not include a $25 handling charge for each shipment, or the actual shipping costs, which are additional. Characteristics of the product: - 3 millicuries per milliliter A t present shipments a r e made on Friday for use on Monday to allow for decay of contaminating 66Ga. Gallium-66 is initially present in high concentration but because of its shortgg half life (9.5 hr) it has decay at the time that the amount left at one day’s dec possibility for reducing the ‘%a; using it would require recovering the target zinc and the economic merits of this option are not clear at present. to less than 1%of the activity G a i s used. Charges for the “Ga e calculated for the after shipping. Enriched “Zn as a target is a Dr. Marvin Kastenbaum, a biomathematician from ORNL who is expected to be able to sarve a s consultant to the group, gave a brief and very well received talk. He made the following points, among others: can be given about numbers needed until experiment is under design; this can be incorporated a s plans develop. Size of sample is exceedingly important; no simple statement 2. Mistakes a r e made in relation to hypotheses a. Accepting fahe ones b. Denying true ones 3. W e are trying to derive meaningful odds; to do this we must 4. “Prestige i s no substitute for truth. ”

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Shortly before 11:00 a.m. the initial part of the meeting w a s concluded and Dr. Robert Greenlaw presided for the rest of the day. H e w a s highly effective in helping the group to organize its thoughts and establish a plan of action. A t this point and at various times during the day there was discussion of the objectives and scope of the project. The consensus appeared to be that the objective w a s "to improve the diagnosis and treatment of cancer by a coowrative effort to evaluate radiopharmaceuticals that localize in neoplasms. '' With 67Ga as an initial focus, it and various comparable agents would be examined in an effort to answer the questions listed earlier. An outline of material to be considered was developed. 1. Identification of the cooperative group. The concensus w a s that the medical schools in ORAU should initiate the project and set up protocols but that any reputable institution would be welcome to participate in the study. 2. Aspects of the radiopharmaceutical to be considered (67Ga initially) a. Physical features, pharmacology, physiology b. Characterization of human radiation dose c. Standardization of radiation dose 3. Characterization of the diseases under consideration 4. Reporting and evaluation 5. Administrative resources, support, timing After this outline had been developed it was decided that after lunch the participants would break up into task groups (as indicated above) and after an hour's work would report back to the larger group. A t this point some informal comments were made by Hayes, Swartzendruber, (ORAU), David Brown (ORNL) and Nelson (ORAU) on mechanisms of distribution. Much work is going on at ORAU and in collaboration with ORNL on this problem. Important approaches include tissue fractionation by ultracentrifugation and studies with electron microscopy combined with autoradiography. Much of the gallium in normal and abnormal tissues appears to be in cytoplasmic structures believed to be lysosomes. This correlates with the fact that the gallium is in a subcellular fraction high in acid phosphatase. Some phagocytic

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cells, perhaps particularly those associated with malignant tissue, show a high uptake of gallium. The element is also concentrated in the malignant cells themselves; the relative importance of these mechanisms of localization probably varies with different animal (and perhaps human) neoplasms. After lunch the task groups met for one hour to discuss the topics assigned to them. When the entire group reassembled, the chairman of each group presented their conclusions. The group felt that a standardized 67Ga pharmaceutical product should be provided to the participants of the cooperative program since if each participating organization prepared their own pharmaceutical there w a s a chance that differences in product quality could exist. Some participants also indicated that they might not be able to prepare their own 67Ga pharmaceutical. There w a s a strong sentiment for having ORAU, working with ORNL, provide a product ready for administration to patients. Arthur Rupp of ORNL believes that ORNL might be able to provide a product that would only require ORAU to test for sterility and pyrogenicity. Since ORNL could not certify the product as suitable for human use, ORAU would have to provide the certification. D r . Andrews stated that ORAU is not unwilling to do this, but he does not know about the legal implications. These would have to be investigated. ORAU would also require some financial support for actual costs. The possibility of having a commercial firm provide the 67Ga pharmaceutical w a s discussed, but this plan was looked on with disfavor for a variety of reasons. The group hoped that a common FDA-IND form might be possible as this would greatly reduce the amount of paperwork required of each participant. A common FDA-IND would also simple the arrangements each group has to make with their own The group felt that specific responsibilities should be assigned to each group and that a "Gallium Newsletter" would be helpful in keeping all groups informed of progress. The decay characteristics of 67Ga a r e sufficiently well known to provide the physical data required for the calculation of radiation dose. What is now required is the distribution of gallium in humans. Extensive distribution data are ahead available at ORAU from studies in cancer patients. Before g7Ga is

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administered to persons only suspected of having cancer, there would be a need for distribution data from normal individuals. Some of the "normal" distribution information might be generated by administering gallium to patients having serious but noncancerous disorders. (There is difference of opinion about the value and ethical aspects of this). Since distribution data for the normal will initially be quite limited, detailed distribution data should be obtained from a primate o r perhaps a large mammal such as a pig. 3. Standardization of Instrumentation A l l of the groups felt that standardization of instrumentation would be required. Initially a list of available equipment will be required. Each group would be asked to provide specific scans applicable to their equipment. Total body scans would be desirable whenever possible. To allow intercomparison among institutions, a phantom would be required. Although it might be desirable to have a "mock 67Ga" source with a long half-life, this prospect seems unlikely because of the complicated decay of 67Ga. Actual Gallium-67 standards would probably have to be inserted into the phantoms. Discussion at this point concerned the possibility of giving tracer doses to some patients without malignancies who could serve a s "normals. I' For studies on sub-cellular fractionation of radioactivity Dr. David Brown would like to receive 10-gram samples of fresh malignant tissue preferably from operations (rather than autopsies) on patients who have received 67Ga. Group B: Bob Greenlaw reporting. 1. The studies should initially be done on cancer patients o r cancer suspects who a …