REPORTS ON SEMINARS

(1) Seminar on “New Advances in Radiation Oncology”

This meeting was held in San Francisco at the University of California’s Laurel Heights Conference Center between February 13 and 15, 1995. It was designed to bring together leading scientists in the various areas of rapid development in radiation oncology from Japan and the United States.
Session A: Boron Neutron Capture Therapy
The first session concentrated on boron neutron capture therapy. Dr. Kochi Ono presented two papers related to boron capture therapy. They are using an experimental mouse squamous cell carcinoma.. He found that boronated phenylalanine distributed heterogeneously in tumors with particularly low uptake in Q cells. More uniform distribution was found for BSH. He then reported on 37 patients treated at the Kyoto Reactor with boron capture therapy using the drug BSH. Treatment was with an open skull and using thermal neutrons. For glioblastoma, the median survival was approximately 9 months in a group of 24 patients.
Dr. Hiroshi Fukuda then reported on their experience with BNCT of malignant melanoma using BPA. A dose of 18 RBE-Gy was used in 9 patients and 6 of 9 had complete response.
Dr. Wllliam Chu presented a novel new design for an accelerator source of epithermal neutrons for BNCT. This machine will be built at LBL using partially surplus parts from an older accelerator and should deliver between 10 and 20 milliamperes of 2.5 MeV protons which would produce sufficient flux similar to reactor sources for BNCT.
Dr. Stephen Kahl then presented information on the development of newer drugs for BNCT, including boronated porphyrins and boronated llpoproteins which seem to have much higher tumor to blood and tumor to brain ratios than in the previously used compounds.
The BNCT programs in the U.S. and in Japan appear to complement each other well. The Japanese are using thermal neutrons and the two American sites at Brookhaven and MIT are using epithermal neutrons which do not require opening the scalp for treatment. It appears likely that some of the Japanese investigators will switch in the future to modified reactors with epithermal neutrons as well.
Session B: Particle Radiotherapy
The second session concentrated on a review of particle radiotherapy in the U.S. and in Japan. Kiyomitsu Kawachi reported on the development of a medically dedicated heavy ion facility at Chiba. This facility has vertical and horizontal beams and produces ions ranging from helium to neon and heavier. The clinical trials are starting with carbon ions and they plan to concentrate on this ion as a major initial research goal. This is now the only heavy ion treatment facility in the world. It is a beautifully designed and built facility with extremely high reliability. There are great expectations for important phase III trials here in the future to continue the work that was begun at the phase I and II level at Lawrence Berkeley Laboratory in the U.S.
Dr. Herman Suit then reviewed the proton radiotherapy program in the United States. There currently are 3 facilities. The first is at Massachusetts General Hospital/Harvard Cyclotron and is limited to tumors of 15 cm or less below the surface. It has achieved an outstanding series of results in tumors in the skullbase and in prostate cancer. A whole new facility is about to be constructed at Massachusetts General Hospital which will be a dedicated proton facility with rotating gantries. The second facility is at Loma Linda University and has rotational gantries and is powered by a synchrotron, whereas the one at Massachusetts General will be powered by cyclotron. The third facility is at U.C. Davis and is designed primarily to treat ocular melanoma with a 60 MeV proton beam. This has currently treated approximately 50 ocular melanomas over the past year.
Dr. Joseph Castro then presented a review of the outcome of treatment of the patients at Lawrence Berkeley Laboratory The accelerators which were used in the trial have now been closed down by the Department of Energy and the patients are in long-term follow-up. Major benefits were shown for ocular melanomas, skullbase tumors, salivary and minor salivary gland tumors; and there were promising results for biliary tumors and sarcomas among others using heavier ions, i.e. neon. At this point it appears that the United States will be concentrating on proton trials at three and probably more facilities over the next 5 years, although the Japanese will concentrate in the short-term on heavy particles. There are several plans for proton accelerators in Japan, as well, and there is a research proton facility at Tskuba.
Session C: Radiosurgery
The third session was dedicated to the topic of radiosurgery, both linear accelerator and gamma knife based. This new technique, which generally delivers a single dose of radiation to limited size tumors and vascular malformations in the cranial cavity, has seen a great upsurge over the last 5 years. This session dealt with development of the systems, the experience and patient results in the U.S. and Japan.
Hiroki Shirato reported on the development of stereotactic fractionated radiotherapy systems. They showed that it was possible to have the patient wear a halo ring for several weeks and that the results appear to be comparable to that of gamma knife treatment.
Dr. Shirato then continued on another paper with a survey of stereotactic fractionated radiotherapy and single high-dose radiosurgery in Japan. They concluded that in the treatment of AVM (arteriovenous malformation), fractionated radiotherapy did not show any benefit as cornpared to single dose gamma knife or linac radiosurgery. They also concluded that for benign tumors, such as acoustic neuromas, fractionated radiotherapy might be as effective as single-dose radiosurgery with less complications.
Dr. Todd Wasserman then reported on stereotactic radiosurgery with linear accelerators in the United States. He described the RTOG radiosurgery quality assurance guidelines, the dose escalation study by RTOG to establish the maximum tolerated dose for small, medium and large volumes, and then a new proposed study for radiosurgery with etanidazole (SR-2508) for the treatment of recurrent primary and metastatic CNS tumors. The RTOG is also now actively conducting a study looking at the use of stereotactic radiosurgery boost following conventional radiotherapy with BCNU for malignant gliomas.
Dr. David Larson then described the experience with gamma knife radiosurgery in the United States, summarizing the large numbers of patients treated and the obvious benefit that has already been shown for AVM’s, brain metastases and the meningiomas and acoustic neuromas. Results with gamrna knife also appear comparable to that of Implant in the treatment of glioblastoma multiforme.
Dr. John Adler from Stanford University described the Accu-Ray system for stereotactic treatment. This novel design uses a robot on which is mounted a linear accelerator so that the beam may come from any possible angle. The entire system is computer-controlled and is designed to target the slightest modest movements of the patient.
Dr. Masao Tago then described experimental studies of gamma knife treatment in rats and particularly emphasized the sizes of the lesions created with the 4 mm collimator of the gamma knife unit.
Dr. Atsuro Terahara then described the results of gamma knife therapy at the University of Tokyo Hospital which are comparable to those throughout the world.
It appears that radiosurgery has now become an important method of treatment in both the United States and Japan, and that its usefulness is being explored far beyond the original indications of AVM’s and benign skullbase tumors. Particularly interesting are the results in brain metastases and in gliomas, and future research will probably concentrate in this area.
Session D: Conformal Therapy/Dynamic Therapy
Session D concentrated on conformal three dimensional radiotherapy and dynamic intensity modified three dimensional therapy. Dr. Kozo Morita described the development of conformal radiotherapy in Japan and the clinical evaluations of this treatment to date. He indicated that over 80 treatment machines in Japan have multileaf collimators because of the long history of the development of this technique since 1957. He concluded that for standard treatments conformal therapy with a few stationary fields using the multileafcollimator is satisfactory. Dynamic conformal techniques are indicated for concave or sophisticated target shapes, or deep-seated targets in radiosensitive organs. He emphasized the types of conformal radiotherapy, including standard and dynamic and coplanar, as well as noncoplanar.
Dr. Allen Lichter then described the highly sophisticated University of Michigan system for the delivery of conformal three dimensional therapy with particular emphasis on noncoplanar beams at the University of Michigan. He emphasized the advantage of conformal radiotherapy for the treatment of prostate cancer and its potential in head and neck, brain and lung cancer. This technique has come of age and now it is important to develop dynamic intensity modulation to further advance the technique.
Dr. James Purdy discussed the RTOG quality assurance program for three dimensional conformal therapy. Nine centers have been funded by the National Cancer Institute to study prostate cancer and they have successfully implemented a system by which all treatment plans, CT scans, etc. are sent to a central review group at Washington University in St. Louis. This will quickly aid in standardizing techniques of three dimensional Radiotherapy, as well as the techniques for tumor and target definition.
Dr. Lynn Verhey described intensity modulated treatments with a multileaf collimator and an inverse planning system. This present device sold by the NOMOS company treats two 1 cm slices simultaneously and continuously modulates the intensity during a rotation. The patient is then translated and another two slices are treated. This system demonstrates the ability to clearly conform the dose distribution to the target and indeed treat multiple targets with good confirmation. It is likely that this will be extended to use with multileaf collimators so that the entire volume may be treated at the same time.
Dr. Keiichi Nakagawa described treatment verification using megavoltage computed tomography in rotational conformal radiotherapy. He concluded that several limitations remain to be solved. The method is a useful tool for treatment verification of high accuracy radiation therapy.
Finally Dr. Gerald Hanks from the Fox Chase Cancer Center described improved survival as measured by the biochemical outcome of the PSA tests in prostate cancer when comparing conformal therapy to conventional radiotherapy. It appears that conformal therapy is likely to be superior in the treatment of prostate cancer to previous methods.
Three dimensional conformal radiotherapy and the next generation of this three dimensional conformal radiotherapy with dynamic beam modification is being rapidly developed in the U.S. and in Japan. It seems to hold a great promise for increasing the dose to tumor and decreasing the dose to critical normal structures. The outcome is likely to be improved but clinical trials will be required to prove this.
Session E: Development of New Radiotherapy Systems
Session E concentrated on the development of new radiotherapy systems, particularly emphasizing CT simulation and portal imaging. Dr. Yasushi Nagata concluded that a CT simulator system allows optimum utilization of CT information and the development of accurate three dimensional plans. He felt that a CT simulator is essential for radiotherapy. The heart of this system is the immediate transport of CT images of the patient to multi-image monitors and the planning computer while the patient remains on the CT scanner couch.
Dr. James Purdy described the integrated radiotherapy network at Washington University which allows close linkage of the 3-D plauning functions, treatment verification and the CT simulation system. This kind of network appears to be highly desirable for future departments which will have heavy imaging data requirements.
Dr. Lynn Verhey described the complexities of managing the information flow that is required for not only conformal and dynamic therapy and all of the images used in its planning, but in all of the other information required for the clinic.
Following Dr. Verhey, Dr. Kaoru Okajlma discussed the development of an integrated radiotherapy data network at Kyoto University. The current system is comprised of a picture archiving and communication system (PACS), a CT simulator, a radiotherapy database system, a simulator, a linear accelerator with multileaf collimation, and electronic portal imaging device (EPID) and a video camera.. The data communication between these devices was developed on Ethernet with a TCP/IP protocol. He concludes that the system is a practical 3-D radiotherapy network which provides accurate treatment delivery with little operator assistance.
Dr. Vernon Smith then described the design of a radiotherapy picture archiving system with emphasis on high storage capacity and rapid transmission of data.
Dr. Kaoru Okajima followed with a description of a PACS system at Kyoto University. He concluded that a PACS system is quite useful for clinical applications in radiotherapy. The basic functions of the system are to transfer, store and display images. These images include not only CT simulator and film digitizer images, but also electronic portal images.
Dr. Yasushi Nagata described the clinical applications of an electronic portal imaging device. This EPID was a liquid ionization chamber system. The minimum spatial resolution was 1.25 mm as compared to 0.5 mm for a screen film system. The minimal contrast resolution was also lower for the EPID system. They concluded that further development of hardware and software are required for clinical applications of the EPID.
Dr. Timothy Schultheiss described the PACS system now in use at Fox Chase Cancer Center which emphasizes particularly the use and analysis of EPID images. They found this device to be extremely valuable in describing errors in patient set-up and patient motion and feel that it would be an important component of any future PACS and total computer network in a radiotherapy department.
It is clear that the application of computers in radiotherapy departments is progressing very rapidly. Outside of treatment planning and dynamic delivery, the important areas are CT simulation, PACS for radiotherapy, and the integration of all of this information and all of these images with the clinical information in order to reduce costs, speed through put and increase accuracy.
Session F: Brachyiherapy
Session F concentrated on modern developments in brachytherapy. Dr. Patrick Swift described the experience with the pulsed dose rate remote afterloader at UCSF. Over 60 patients have been treated and it appears that pulsed treatment using iridium which delivers approximately 60 cGy in a single pulse each hour lasting 10 minutes or less is equivalent to conventional low dose rate continuous irradiation, both in terms of tumor response and normal tissue reactions.
Dr. Toshihiko Inoue then described a phase III study being conducted in Japan comparing high and low dose rate interstitial radiotherapy for tongue cancer. He concluded that 2-year local control rates, based on over 33 patients entered into this study, were 86% for low dose rate and 100% for high dose rate respectively. In spite of the small number of patients, it would appear that fractionated high dose rate (HDR) interstitial brachytherapy is a satisfactory alternative to traditional low dose rate (LDR) brachyiherapy for early tongue cancer. They employed an HDR scheme of 60 Gy in 10 fractions over 6 days.
Dr. Takayuki Nose presented a study which described HDR fractionated interstitial brachyiherapy for oropharyax cancer. Eleven patients were treated by a combination of HDR and external beam irradiation with 8 of 11 controlled. They employed a dose of 46 Gy external beam with twice daily fractionated HIDR using 8 fractions with doses ranging from 28 to 48 Gy. They found that 48 Gy in 8 fractions was satisfactory for base of tongue, but it may be that lower total doses are required in the tonsillar and palatal region.
Dr. Devron Char then presented the results of a comparison of iodine plaque brachytherapy to particle irradiation with helium ions for ocular melanoma. This study revealed that local control is better for the charged particles but that there was a higher incidence of complications due to neovascular glaucoma.
Dr. Don Goffinet then reported on the use of brachyiherapy using low dose rate (LDR) for base of tongue cancer with outstanding local control results.
It appears that excellent advances are being made in brachyiherapy, particularly in using HDR as a replacement for LDR with the concomitant reduction in nursing problems and in patient discomfort. Pulsed dose rate (PDR) appears equivalent to LDR and allows much more accurate tailoring of dose distribution, as well as less problems with nursing care. It remains to be seen whether fractionated HDR or PDR will become the main stay of brachyiherapy in the future.
Session G: Intraoperative Radiotherapy
Session G then dealt with the current techniques and results with intraoperative radiotherapy (IORT). Dr. Tyvin Rich from M.D. Anderson Hospital described the results of a wide range of IORT studies for pancreatic and rectal cancer at M.D. Anderson and concluded that there appear to be benefits from this technique.
Dr. Jerome Vaeth then described the development of a portable IORT system for use in non-shielded operating rooms. The system will use a lightweight linear accelerator on a mobile C arm and is designed to have very low x-ray generation so that it can be used on almost any operating room without additional shielding. It has the potential for bringing IORT much more widely into the standard armamentarium of the surgeon and radiation oncologist.
Dr. Yoshiaki Tanaka then reported the results of intraoperative radiation therapy for carcinoma of the pancreas and bile duct. They concluded that the combination of external beam irradiation and IORT prolongs the survival of patients. They also concluded that aggressive resection of the tumor in addition to the radiotherapy is extremely important.
It appears that the use of IORT is becoming standardized in certain sites and benefits are particularly evident in rectal cancer and in certain biliary tumors, as well as in head and neck and possibly pancreas cancer. The development of a portable IORT machine should markedly advance this field.
Session H: Diagnostic Imaging in Radiotherapy
Session H reviewed the impact of diagnostic imaging on radiotherapy. The session particularly emphasized the importance of positron emission tomography (PET) and magnetic resonance imaging (MRI) in radiotherapy treatment planning and the evaluation of response.
Dr. Hiroshi Fukuda reported on the use of PET scanning; first of all to estimate proliferative activity of the tumor and to biologically characterize the tumor. He emphasized the usefulness of PET in tumor detection, differential diagnosis between benign and malignant, monitoring of tumor response and diagnosing differentially between local recurrence and scar formation. PET scanning appears to be important in all of these areas.
Dr. Randall Hawkins emphasized that whole body PET fluorodioxyglucose imaging has great potential for mapping the distribution of cancer throughout the whole body.
Dr. Hedvig Hricak emphasized the importance of imaging in the treatment of prostate cancer. Of particular importance is transrectal ultrasound and transrectal MRI in delineating the exact extension of the tumor which can be quite useful in radiotherapy treatment planning.
Dr. Jeanne Quivery expanded this position in her description of the role of MRI in the staging and prognostic prediction of outcomes in carcinoma of the cervix. It would appear that MRJ staging is far more accurate than clinical staging.
This session emphasized the importance of modern imaging techniques in radiation oncology. Both PET scanning and MRI will allow much more accurate diagnosis of not only local extension but particularly distant and regional disease than is currently possible with conventional clinical and radiographic techniques.
Session I: Chemical Modifiers of Radiation
Session I concentrated on the review of clinical trials of chemical modifiers of radiation therapy. Dr. Todd Wasserman reviewed the current status of radiation modifier studies in the United States. He emphasized the ongoing study of high dose etanidazole with intraoperative irradiation, as well as the recently completed etanidazole study in head and neck cancer which gave a null result. It is likely that etanidazole will be primarily useful as a single high dose with IORT or with radiosurgery. Other ongoing studies include the use of bromodeoxyuridine in anaplastic astrocytoma and a future study of tirapazamine in glioblastoma..
Dr. Martin Brown emphasized the particular importance of hypoxic cell cytotoxins. Tirapazamine is one of these. These are drugs that are activated in hypoxic cells of tumor and may be administered before or after radiotherapy. They have potential both with radiotherapy to kill all of the remaining hypoxic cells and with chemotherapy to kill what are potentially resistant cells to chemotherapy.
Dr. Allen Lichter reviewed the studies of halogenated pyrimidines at the University of Michigan which are particularly emphasizing the treatment of liver metastases with promising results.
Dr. Michael Prados reviewed the halogenated pyrimidine studies at UCSF which have included the evaluation of cell kinetics in brain tumors, phase II studies of the usefulness of bromodeoxyuridine in anaplastic astrocytoma and glioblastoma, and a current study evaluating various administration schemes and a comparison of IUDR and BUDR for uptake in malignant brain tumors. He concluded that these drugs are very useful in studying the biology of brain tumors and may well have a major role to play in the treatment of anaplastic astrocytoma.
Dr Yuta Shibamoto then reviewed the present status of hypoxic cell sensitizer development in Japan. He described the study of a fluorinated 2 nitroimadazole and a newer 2 nitroimadazole nucleoside which appears to be superior. It is expected that this compound will be at least as active as etanidazole with less toxicity. Clinical trials will begin in 1995.
Dr. Gerald Hanks then described the potential for a combined treatment of advanced prostate cancer which involved patients with high PSA levels and includes taxol, estramustine, androgen deprivation and extensive radiotherapy. This approach is based on the failure patterns of such patients and is now under active investigation.
It would appear that the hypoxic cell sensitizers such as etanidazole have been proven inadequate for fractionated radiotherapy because of the low dose per fraction which can be administered. Halogenated pyrimidines still have promise in certain malignant brain tumors and are under study in randomized trials and are being evaluated in other tumors such as liver metastases. The hypoxic cell cytotoxins are now ready for wide scale clinical evaluation and in the next few years major studies will be conducted with tirapazamine.
Session J: New Approaches to Clinical Trials
Dr. Allen Lichter first described the long term results of the NCI trial which compared mastectomy to limited excision and radiotherapy in breast cancer. When it was first started, it was a pioneering trial and now with 10-year data, it appears clear that the two approaches are equal in terms of survival.
Dr. James Cox then described the Radiation Therapy Oncology Group (RTOG) and its wide acceptance throughout the United States and very large numbers of members. He reviewed the current studies and the outcome of previous studies in brain, cervix, gastrointestinal, genitourinary, head and neck, and lung cancer. RTOG research strategies have concentrated on solutions to radiation tumor control problems induced by the effects of oxygen deprivation, rapid tumor cell kinetics, the need for dose escalation, and the use of radiation enhancers. He also emphasized the goals of the group in terms of organ preservation.
Dr. Yuko Akagi then described his results with definitive radiation therapy for esophageal cancer with emphasis on HDR intraluminal irradiation. He described 21 patients who were treated with either intraluminal only or in combination with external beam irradiation. Five patients with very superficial tumors were treated with intraluminal brachytherapy only and 16 patients had intraluminal boost after external beam irradiation. All of the patients with superficial tumors were controlled with intraluminal irradiation alone and only 2 of the 16 patients with combined treatment have failed.
Dr. Ritsuko Komaki discussed the results in clinical trials of carcinoma of the lung for both non-small cell and small cell lung cancer. She particularly emphasized the results of RTOG studies. Gains have been made in this disease so far by the addition of neoadjuvant chemotherapy and current studies are comparing neoadjuvant to simultaneous chemotherapy with radiotherapy. In small cell lung cancer, it appears that early use of radiotherapy with concomitant chemotherapy is important.
Drs. Mitsuyuki Abe and Yasushi Nagata then described new approaches to breast conservation with particular emphasis on the use of the CT simulator in planning radiotherapy treatments for breast conservation. They presented data supporting the conclusion that CT simulation improved the results of breast irradiation in conservation therapy.
Clinical trials appear to be highly organized in the United States, particularly in the RTOG, in radiation oncology. Clinical trials in Japan appear to be more institution-based than multi-institution, but in this system also, interesting results are emerging particularly for esophageal and breast cancer.
Session K: Hyperthermia
Session K concentrated on the results of modern era hyperthermia. Dr. Leonard Prosnitz reviewed the approach at Duke University which involves particular emphasis on the definition of thermal dose and new protocols which will test the ability to deliver a prescribed thermal dose and then the outcome in patients in whom that thermal dose can be achieved. This should allow for a better evaluation for hyperthermia than has been previously possible.
Dr. William Dewey described the concept of thermal dose and its relationship and presented information indicating that much higher thermal doses are required as well as higher thermal doses in tumor centers and at tumor peripheries.
Dr. Penny Sneed presented results of a phase II trial at UCSF with interstitial irradiation in malignant brain tumors and the interim results of a randomized trial comparing interstitial boost for glioblastoma multiforme to Interstitial boost with hyperthermia. The outcome appears closely related to thermal dose and there has been a constant improvement in the size of the thermal dose which can be delivered over the 5 years in which these 2 studies have been conducted.
Dr. Satoru Uehara described the outcome of thermal radiotherapy for carcinoma of the cervix using a phased array device The outcome was measured by histopathological changes obtained on biopsy. The results indicated that hyperthermia enhanced the radiation damage.
Dr. Yoshiaki Tanaka then described clinical experience with an RF capacitive heating device in deep seated tumors. He emphasized the importance of quality assurance for hyperthermia so that a better comparison of inter-institutional results could be obtained.
It appears that hyperthermia is finally developing a dose definition that will allow prediction of outcome and allow for much more standard clinical trials in the future. The CEM 43 degree T90 appears to be the best candidate for a thermal prescription and it would appear that doses of at least 10 and possibly even 100 CEM 43 degree T90 are required for optimal clinical response.
Session L: Molecular Radiobiology
Session L concentrated on molecular radiobiology. This was a very exciting session with multiple speakers who first described the expression of oncogene products in cancer tissues, patients undergoing radiotherapy, the application of cytogenetic techniques in cancer prognosis and the effect of radiation in altering the expression of oncogene products in liver, spleen, kidney and brain. These first studies were presented by Dr. Yasuhiro Ogawa and Dr. Joe Gray.
Dr. Philip Rubin described the molecular basis of radiation reaction in the lung. Radiation pneumonitis appears to be an extremely complex event which begins soon after irradiation with the release of multiple cytokines which control the development of the reaction and its healing.
Dr. Gillies McKenna described the molecular mechanisms involved in radiation resistance. It appears that it is extremely important to understand these mechanisms in order to be able to modify them and then modify the sensitivity of the tumor.
Dr. Tyvin Rich described the incidence of apoptosis in rectal cancer. Building on the importance which Dr. McKenna had assigned to apoptosis, he indicated that this is an important mechanism in the death of rectal cancer cells.
Dr. Michael Christman then described the Induction of signals via ionizing radiation and its relationship to the defect present in ataxia telangiectasis.
Dr. Bruce Feuerstein returned to the theme that Dr. Gray had begun and emphasized the genetic changes which were seen in malignant gliomas. They are myriad and involve many different chromosomes. Understanding these changes will be extremely important in developing new therapies.
Dr. William Morgan discussed the mechanisms of repair of DNA and chromosome damage. Particularly important is radiation-induced delayed chromosomal instability that can continue in the progeny of cells surviving the initial radiation exposure.
The session ended in a roundtable discussion. It is an extremely exciting and quite confusing area. Many leads have been found which will provide new insights into the effects of radiation and new techniques for improving its effectiveness in tumors and reducing its injurious effects to normal tissues. It would appear at this time that the most Important thing is to understand the genetic abnormalities in tumor in terms of tumor response to treatment and understanding radiation damage repair and possible modification. Finally, apoptosis may also be an extremely important event and its understanding and control will be highly developed over the ensuing years.
The meeting clearly reviewed the important topics in radiation oncology today in the U.S. and Japan. There appears to be convergence of focus on three-dimensional planning, dynamic dose distribution, computerized systems for image and information exchange within the department and departments and continued interest in the development of radiation modifiers such as hypoxic cytotoxins and hyperthermia. The future appears to lie m a great expansion of the efforts in the study of molecular radiobiology. It could be predicted that in 10 years, there will be equal importance of molecular biology and advances in physics and imaging yielding continued improvement in the results of radiotherapy.

PARTICIPANTS

UNITED STATES

Dr. James D Cox
Department of Radiotherapy
M.D. Anderson Cancer Center
Houston, TX

Dr. Gerald E. Hanks
Department of Radiation Oncology
Fox Chase Cancer Center
Philadelphia, PA

Dr. Ritsuko Komaki
Department of Radiotherapy
M.D. Anderson Cancer Center
Houston TX

Dr. Allen S. Lichter
Department of Radiation Oncology
University of Michigan
Ann Arbor MI

Dr. W. Gillies McKenna
Department of Radiation Oncology
Hospital of the University of Pennsylvania
Philadelphia, PA

Dr. Leonard Prosnitz
Department of Radiation Oncology
Duke University Medical Center
Durham NC

Dr. James A Purdy
Department of Radiation Oncology
Mallinckrodt Institute of Radiology
St. Louis, MO

Dr. Tyvin A. Rich
Department of Radiotherapy
M.D. Anderson Cancer Center
Houston TX

Dr. Philip Rubin
Department of Radiation Oncology
University of Rochester
Rochester, NY

Dr. Timothy Schultheiss
Department of Radiation Oncology
Fox Chase Cancer Center
Philadelphia, PA

Dr. Herman Suit
Department of Radiation Oncology
Harvard Medical School at Massachusetts General Hospital
Boston, MA

Dr. Todd H Wasserman
Department of Radiation Oncology
Mallinckrodt Institute of Radiology
St. Louis, MO

Dr. John Adler
Department of Neurosurgery
Stanford University Medical Center
Stanford, CA

Dr. J. Martin Brown
Department of Radiation Oncology
Stanford University Medical Center
Stanford, CA

Dr. Joseph Castro
Lawrence Berkeley Laboratory
Berkeley, CA

Dr. Devron Char
Department of Ophthalmology
University of California at San Francisco
San Francisco, CA

Dr. Michael Christman
Radiation Oncology Research Laboratory
University of California at San Francisco
San Francisco, CA

Dr. William Chu
Lawrence Berkeley Laboratory
Berkeley, CA

Dr. William C Dewey
Radiation Oncology Research Laboratory
University of California at San Francisco
San Francisco, CA

Dr. Burt Feuerstein
Department of Laboratory Medicine
University of California at San Francisco
San Francisco, CA

Dr. Don R Goffinet
Department of Radiation Oncology
Stanford University Medical Center
Stanford, CA

Dr. Joe W. Gray
Department of Laboratory Medicine
Division of Molecular Cytometry
University of California at San Francisco
San Francisco, CA

Dr. Randall A. Hawkins
Department of Radiology
University of California at San Francisco
San Francisco, CA

Dr. Hedvig Hricak.
Department of Radiology
University of California at San Francisco
San Francisco, CA

Dr. Stephen B. Kahl
Department of Pharmaceutical Chemistry
University of California at San Francisco
San Francisco, CA

Dr. David A, Larson
Department of Radiation Oncology
University of California at San Francisco
San Francisco, CA

Dr. William Morgan
Laboratory of Radiobiology and Environmental Health
University of California at San Francisco
San Francisco, CA

Dr. Theodore L. Phillips
Department of Radiation Oncology
University of California at San Francisco
San Francisco, CA

Dr. Michael D Prados
Neuro-Oncology Department
University of California at San Francisco
San Francisco, CA

Dr. Jeanne M. Quivey
Department of Radiation Oncology
University of California at San Francisco
San Francisco, CA

Dr. Vernon Smith
Department of Radiation Oncology
University of California at San Francisco
San Francisco, CA

Dr. Patricia K Sneed
Department of Radiation Oncology
University of California at San Francisco
San Francisco, CA

Dr. Patrick S Swift
Department of Radiation Oncology
University of California at San Francisco
San Francisco, CA

Dr. Jerome Vaeth
Department of Radiation Oncology
St. Mary’s Hospital and Medical Center
San Francisco, CA

Dr. Lynn J. Verhey
Department of Radiation Oncology
University of California at San Francisco
San Francisco, CA

JAPAN

Dr. Mitsuyuki Abe
Director
Kyoto National Hospital
Kyoto

Dr. Hiroshi Fukuda
Chairman
Department of Nuclear Medicine and Oncology
Tohoku University
Sendai

Dr. Yukio Akagi
Department of Radiology
Hiroshima University
Hiroshima

Dr. Toshihiko Inoue
Chairman
Department of Radiation Oncology
Osaka University
Osaka

Dr. Kiyomitsu Kawachi
Director
Division of Accelerator, Physics and Engineering
National Institute of Radiological Sciences
Chiba

Dr. Kozo Morita
Director
Research Center for Charged Particle Therapy
National Institute of Radiological Sciences
Chiba

Dr. Yasushi Nagata
Department of Radiology
Kyoto University
Kyoto

Dr. Keiichi Nakagawa
Department of Radiology
University of Tokyo
Tokyo

Dr. Takayuki Nose
Department of Radiology
Osaka University
Osaka

Dr. Yasuhiro Ogawa
Kochi Medical School
Kohasu Oko-cho, Nankoku-shi

Dr Kaoru Okajima
Department of Radiology
Kyoto University
Kyoto

Dr. Koji Ono
Chairman
Radiation Oncology Research Laboratory
Research Reactor Institute
Kyoto University
Osaka

Dr. Yuta Shibamoto
Department of Oncology
Chest Disease Institute
Kyoto University
Kyoto

Dr. Hiroki Shirato
Department of Radiology
Hokkaido University
Sapporo

Dr. Masao Tago
Department of Radiology
University of Tokyo
Tokyo

Dr. Yoshiaki Tanaka
Chairman
Department of Radiology
Nihon University
Tokyo

Dr. Atsuro Terahara
Research Center of Charged Particle Therapy
National Institute of Radiological Sciences
Chiba



Dr. Satoru Uehara
Department of Radiology
Kyushu University
Fukuoka

Attendees:

Yoshio Hishikawa

Naonobu Kunitake

Other attendees:

Mary Louise Meurk
West Coast Cancer Foundation
San Francisco, CA

UCSF Faculty

Representatives from IntraOp Inc., Mitsubushi Co., Siemens Medical Systems, and Varian Systems



(2) Seminar on “Progress in Treatment of Lung Cancer”

This conference focused on the clinical aspects of lung cancer therapy in Japan and the United States. A total of 30 participants joined in these discussions held at the Aichi Cancer Center in Nagoya, Japan, on January 17 and 18, 1995. Despite the fact that a devastating earthquake occurred only a short distance away, the participants were able to seriously engage in these discussions.
The first session dealt with basic biologic aspects flung cancer. Dr. Bruce Johnson described an elegant series of studies which characterized the in vitro sensitivity of lung cancer cell lines to Taxol. Utilizing an MIT assay he determined the relative efficacy of new agents -- which taxane or which camptothecin. He determine that long exposure (~120 hours) to Taxol was highly effective at killing cells. Based on the in vitro evidence of additive activity of CDDP + Taxol, a pilot study was initiated. Taxol infusions of 35 mg/m² for 4 days and CDDP 80 mg/m² on Day 5 were utilized and so far 9/16 NSCLC patients have had an objective response. He also presented data on the clinical application of antibombesin antibody (2A111) in SCLC patients.
Next, Dr. Takahashi described his studies of genetic analysis of lung cancer patients. A large number of genes are Involved in lung cancer. P53 is involved in more than 80-% SCLC and more than 50% of NSCLC. While there are a variety of P53 mutations, the most frequent are GC ---> TA (SC > NSCLC > LC > Adeno). P53 mutations appear to be a negative prognostic factor for resected patients, and Dr. Takahashi performed a study of 208 patients. This study failed to confirm the prognostic value of P53. Dr. Takahashi also described studies of 3p (14-23) chromosomal abnormalities.
Dr. Kerns presented a discussion of pharmacokinetics in the therapy of lung cancer patients. She described specifically Taxol, Taxol + Carboplatin, VP-16, Topotecan, and CPT-11. While Taxol is an active agent, the correlation between schedule and dose is unclear. Moreover, the 3 hour schedule has more leukopenia than 24 hour schedules (however, AUC was similar). A combination of Taxol + Carboplatin was also explored. For VP-16, responses were associated with duration of exposure of 1.0-20 ug/ml while toxicity is related to AUC of free drug. Clearly for VP-16 the response is related to duration (qd x 1 is less effective than same total dose divided over 5 days). For topotecan no conclusive data exists for response, but for toxicity the ratio of lactone form to total drug may be informative.
Dr. Sasaki described the pharmacokinetics of CPT-11 especially related to diarrhea. He studied 64 patients in detail to define PK and PD features for 100 ug/m² CPT-11. Leukopenia was mild and tolerable. The precise relationship between dose and response was not possible to determine. He also presented data on a new agent, NB506 a Indopyrrocarbazol which appears to inhibit Topoisomerase I. While it has similar structure to Staurosporin, it has no PKC activity. A Phase I study was completed at 80 grn/m² with mild hematologic toxicity. However, fever, hypotension, and LFT changes were noted and were dose limiting.
The session on NSCLC began with Dr. Aisner who discussed new therapeutic approaches. He focused on Stage III (about 40% of all NSCLC and median survival 8-10 months). Comparative trials of RT vs. RT + CT indicate that combined modality approaches are superior. He described both sequential and simultaneous approaches. Studies of combined RT + CT indicated a 3 fold increase in survival at 3-5 years (at least for better risk patients). Drugs such as CBDCA given simultaneously with RT seems to be effective. Studies of CBDCA + Taxol are promising and are now being combined with RT. Overall, about 60% of patients have response to RT + CT.
Dr. Saijo presented a complimentary discussion of new strategies including new agents such as taxanes, taxol, CPT-11, NK 109, NB 506, KW 2189, KRN-5500, etc. Combinations include CPT-11 + VP-16 and CPT-11 + CDDP. A study of 60 mg/m²/d x 3 d for CPT-11 and VP-16 (with OCSF) repeated q3 weeks included 60 patients and PR rate was 23%. This low response rate is not unexpected based on pre-existing preclinical data. Also ongoing are combinations of RT + CDDP/CPT-11 or CDDP/VDS.
Dr. Furuse discussed studies of Stage III NSCLC patients utilizing RT and CT. most recently he is studying concurrent vs. sequential programs. In his hands, CT alone was inferior to CT + RT and hence combined modality is considered necessary. CT consisted of CDDP + VDS + MMC along; with concurrent, split course RT or Post CT, RT, 56 Gy in both arms. A total of 320 patients were randomized and about 75% response rate was noted. A full analysis of this study will occur soon.
Adjuvant and neoadjuvant CT approaches were summarized by Dr. Ichinose. At his Center completely resected IIIA patients received either post-OP CDDP/VDS or nothing. A total of 181 patients were analyzed and no difference was observed in survival (30% 5 year survival). For Stage I adenocarcinoma patients who are completely resected, the randomization is between NFT or nothing. A full range of studies has been proposed for Stage III patients.
Dr. Masuda described a series of studies of new combinations of chemotherapy for NSCLC patients. Combination of CPT-11 and CDDP were most carefully evaluated, and about 50% of patients responded. This combination is even more highly active in SCLC (80-90%) and integration with G-CSF is being explored.
Dr. Devore described 2 drug combinations for NSCLC patients. ECOG study 5592 compared Taxol/UCDDP, VP-16/CDDP and Taxol/CDDP + G-CSF. Taxol was either 175 mg/m2or 250 mg/m² + G-CSF. This study has completed accrual and there were 7/104 deaths in the high dose Taxol regimens, along with a 25% neuropathy rate. For further studies, Taxotere + CDDP, CPT-11 + CDDP and Taxol + CBDCA are under careful consideration.
The second day of the meeting was devoted to SCLC and new agents. Dr. Perry discussed new approaches to patients with limited SCLC. The use of alternating regimens (CAV and EP) has not demonstrated improved survival but new agents must be tested. The use of warfarin added to CT has not been associated with improved outcome. Likewise, while PCI decreases CNS metastases, there is no overall impact on survival and perhaps should be reserved only for CR. With respect to radiation therapy the use of BID RT has not been proven to be superior. But RT should probably be given early in the course of treatment. The number of new agents available are growing and offer many new possibilities. By contrast, the use of hematopoietic growth factors have been disappointing.
A complimentary presentation was provided by Dr. Fukuoka who also believes that CT+RT is superior to CT alone. The JCOG experience with EP+RT in 59 patients was a 41% CR and MDS = 15 months. They are conducting major Phase III trials to examine the timing of RT with EP. For extensive disease patents, Dr. Fukuoka has studied weekly CDDP + G-CSF and noted slightly higher CR rate and MST = 59 weeks for CDDP + G-CSF in 63 patients. He is also examining how to integrate new agents like CPT-11, Topotecan, Taxol, and Gemcitidine into CT programs. A combination of CPT-11 (60 mg/m²) and CDDP (60 mg/m²) yielded a CR rate of 30%, and MST = 12 months, and a randomized comparison to EP is ongoing.
Dr. Ueoka presented comments on prognostic factors in SCLC. Utilizing a complex regimen (COMP/VAN or VAC/PVP) the CR rate was about 30% and MST = 10 months. Performance status weight loss and extent of disease were prognostically significant. Likewise albumin, Hgb, LDH were individually significant. It is possible to lump patients into risk groups of varying prognosis.
Dr. Friedman presented an overview of anti-angiogenic strategies. He first pointed out the background information on the importance of vascular factors and then described a series of new agents which interfere with angiogenesis. The testing of these new agents will be complex since the optimal biologic dose may be different from the maximal dosage.
Dr. Arioyoshi provided the final presentation and comprehensively reviewed new agents being clinically tested in Japan. Especially important were CPT-11, 2545 (cisplatin analogue), Vinorelbine, Taxol, and Gemcitabine. A complex set of two drug studies are being planned, but the optimal combinations are not clearly identified.

PARTICIPANTS

UNITED STATES

Dr. Joseph Aisner
University of Maryland Cancer Center
22 S. Greene Street
Baltimore, Maryland 21201-1544
Tel: (410) 328-2565
Fax: (410) 328-6896

Dr. Michael Perry
Ellis Fischel Cancer Center
115 Business Loop 70W
Room 524 Columbia, Missouri 65203-3299
Tel: (314) 882-4979
Fax: (314) 884-6050

Dr. Bruce Johnson
National Cancer Institute
Chief, Lung Cancer Biology Section
Naval Hospital
Building 8, Room 5101
Bethesda, Maryland 20889-5105
Tel: (301)496-0922
Fax: (301) 496-0047

Dr. Russell Devore III
Vanderbilt University
School of Medicine
21st Avenue South at Garland Avenue
Memphis, Tennessee 37232
Tel: (615) 322-4967
Fax: (615) 343-7602

Dr. Christine Kerns
University of Maryland Cancer Center
22 Greene Street
Baltimore, Maryland 21201-1544
Tel: (410) 328-3685
Fax: (215) 728-2741

Dr. Michael Friedman
Associate Director
Cancer Therapy Evaluation Program
6130 Executive Boulevard, MSC 7438
Rockville, Maryland 20892-7438
Tel: (301)496-6138
Fax: (301) 402-0084

JAPAN

Organizer:
Dr. Yutaka Ariyoshi
Chief, Department of Hematology & Chemotherapy,
Aichi Cancer Center,
1-1 Kanokoden Chikusa-ku, Nagoya, Aichi, 464

Other Participants:
Dr. Makoto Ogawa
Director, Aichi Cancer Center,
1-1 Kanokoden Chikusa-ku, Nagoya, Aichi, 464

Dr. Takashi Takahashi
Chief, Laboratory of Ultrastructure Research,
Aichi Cancer Center Research Institute,
1-1 Kanokoden Chikusa-ku, Nagoya, Aichi, 464

Dr. Sasaki Yoshitsuna
Chief, Division of Oncology/Hematology,
National Cancer Center Hospital East,
6-5-1 Kashinoha Kasiwa-city, Chiba 277

Dr. Fukuoka Masahiro
Chief, Department of Pulmonary Medicine,
Osaka City General Hospital,
2-13-22 Toshima-Hondori, Toshima-ku, Osaka 534

Dr. Hiroshi Ueoka
Assistant Professor. IIed Department of Medicine,
Okayama University, Medical School,
2-5-1 Shikada-cho, Okayama-city, Okayama 700

Dr. Nagahiro Saijyo
Chief, Pharmacology and Medical Oncology,
National Cancer Center Research Institute,
5-1-1 Tsukiji Cyuo-ku, Tokyo 104

Dr. Kiyoyuki Furuse
Chief, National Kinki Center Hospital for Chest Disease,
1180 Nagasone-cho, Sakai-city, Osaka 591

Dr. Yukito Ichinose
Chief, Department of Chest Surgery,
National Kyushu Cancer Center,
3-1-1 Notame Minami-ku Fukuoka 815

Dr. Noriyuki Masuda
Clinical Fellow, Department of Internal Medicine,
Osaka Prefectural Habikino Hospital,
3-7-1 Habikino Habikino-city, Osaka 583



(3) Seminar on “New Anticancer Drugs and MDR Modulators”

This meeting dealt with novel topics in therapeutics development and allowed discussions of innovative biologic interventions. The first session dealt with selected new agents Dr. Raber described a clinical trial of TNP 470, a fumagillin analogue, which is a potent antiangiogenic agent. Preclinical toxicity consisted of weight loss and neuropathy. The Phase I trial was good therapy for hormone refractory prostate cancer patients. Neurotoxicity (confusion) was dose limiting along with profound fatigue. Some patients had decreased PSA, but others had elevation of PSA after each dosage (there was an actual PSA decline in 8 patients after discontinuation of TNP 470) and there was a concomitant increase in basic FGF. Dr. Fine described another TNP470 Phase I study with continuous therapy that did not demonstrate these apparent “tumor flares”.
Next, Dr. Takaku described his studies of MX2, an anthracycline analogue effective in Dox-resistant animal tumors. In patients, the DLT was leukopenia, but thrombocytopenia was also noted. A Phase II study in previously treated AML and ALL patients had a 10% CR rate. Pilot studies combined MX2 with Ara-C and Vcr + Prednisone for frontline therapy are ongoing. Studies with Spikamycin analogues were also presented. This agent is highly active in colon, stomach, and esophageal xenografts. Preclinical studies indicate DNA, RNA, and protein synthesis inhibition (but mostly DNA-RNA). A P388 resistant line is being utilized for mechanism studies. Toxicology reveals GI and hepatic toxicity.
Dr. Ogawa presented data on two new agents. TRK 710 is a platinum analogue with substantial water solubility and activity in CDDP resistant lines. Major toxicity is neuro and hepatic preclinically. The Phase I study is in progress. The agent SM 5887 is a totally synthetic anthracycline analogue. It is water soluble and relatively non-cardiotoxic. Leukopenia was dose limiting. Studies in NSCLC patients were completed and 6/34responses noted. No activity was noted in gastric cancer; but some responses were noted in patients with NHL and Hodgkin’s Disease. A blinded Phase III trial of CHOP vs SMCOP was initiated but was far too small to permit any but the most gross differences.
Dr. Ariyoshi presented an overview of CPT-11 , an interesting new Topoisomerase I inhibitor. The toxicity of this agent is diarrhea and vomiting with less severe leukopenia. As a single agent, CPT-11 has activity in NSCLC, ovarian, cervix, colon, and NHL Combinations with CDDP or 5FU or VP16 are currently being explored. For NSCLC, CDDP 80 mg/m² D1+36 with CPT-11 weekly D1+8… (60 mg/m²), and 14/26 had PR (MDR=82 days). For SCLC substantial responses (30% CR and 50% PR) were noted for this combination. For colon cancer, CPT-11 has a 25% PR rate. When combined with CI 5FU (400 mg/m²/d X 7 days), CPT-11 could be given at 175 mg/m²; and a poorer response rate was noted (10%). Now, a break in treatment interval and higher dose of 5FU (600 mg/m²/d X 7 CI) are being explored. Dr. Hung described studies with Her-2neu targeted therapeutics. The gene Her-2 is overexpressed in breast, ovary, lung, and stomach tumors. The presence of high Her-2 seems to increase the metastatic potential of tumor. All steps of metastasis are enhanced (adhesion, migration, matrix degradation and invasion). Another mechanism is potential chemoresistance leading to poorer survival. Studies of adenovirus 5E1A protein indicate that Her2 can be inhibited (by inhibiting transcription). Transfection with adenoviral 5E1A gene seems to inhibit tumor aggressiveness. Using an adenovirus vector, E1A producing lines are being studied. Another experiment with E1A plasmid DNA in a cationic lipsome (not virus) was also dramatically positive. He is also exploring tyrosine kinase inhibitors to interfere with Her2 (Emodin).
Dr. Harada began the session on hematopoietic reconstitution with a discussion of GCSF and PBSCT. Studies were conducted with CT mobilization or with CT + GCSF. GCSF is not selective mobilizer but it can be enhance the effect of mobilization. Studies of AML cells indicates some GCSF receptor positive but ALL cells are generally negative. A combination program of Ara-C, Busulfan, VP16, GCSF and APBSCT has been initiated. For collecting adequate progenitor cells from normal donors, 10 or 15 microgram/kg of GCSF should be used.
Dr. Mizoguchi then presented his studies of newer cytokines for thrombopoiesis. He discussed IL-3, IL-6, IL-11. Two IL-3 (Sandoz) studies were described for MDS and post-chemotherapy patients. Using CBDCA + VP16 the severity of thrombocytopenia was lessened with ILS-3 (5 g/kg). A study of IL-6 (Serono) examined post-CT thrombocytopenia. Fever and fatigue were noted frequently but some benefits were noted in 6/17 (Phase I study). Toxicity is contributing to this study’s slow progression. Studies of IL-1 1 (Yamanouchi) concentrated on MDS and Aplastic Anemia. Toxicity of IL-11 included mild fever, fatiguability, and injection site irritation. Early data reveals little benefit and little efficacy.
Dr. Shimosaka described studies of Thrombopoetin (TP) and preclinical methods to isolate and clone the gene for TPO. A variety of strategies were used to identify this gene -- rats, pigs, sheep, and dogs (with antiTPO antibodies or irradiation). There is considerable similarity of N-terminal for rat and human and there is no species specificity for effect. Phase I trials in humans should begin soon.
Dr. Tsuruo presented data on KW 2189 (a Quinocarmycin analogue) which appears to have DNA minor groove interactions, alkylator modulation and DNA alkylation. KW 2189 has broad effectiveness in xenografts -- colon, breast, lung, etc. as well as collateral sensitivity with MMC, CDDP, VCI, ADM, CPT. Preliminary toxicity studies suggest acute bone marrow toxicity, and a Phase I study is ongoing in Japan. He also discussed a mechanism of apoptosis resistance as it relates to drug resistance.
Dr. Kuwano described his studies of TopoII alpha agents and MRP resistance. He has characterized multiple lines -- concentrating on podophyllotoxin resistance. Evidence of TopoII alpha decrease was detected in resistant lines and evidence of HSP interactions were noted. Interestingly, both TopoII alpha and MDR-1 genes have inverted CCAAT box and GC box. Both MDR and MRP have ATP binding sites intracellularly and he has isolated cell lines which are MRP resistant.
Dr. Friedman then discussed MDR clinical trials being conducted in the USA. Two agents are being utilized - r-verapamil and PSC 833. Concentration on Phase III studies of hematologic malignancies should provide definitive answers to the general mechanism hypothesis. Recognizing PK/PD differences associated with PSC 833, these definite studies should be difficult but possible.
Dr. H. Fine described a series of interesting experiments with gene therapy approaches. As a pharmacologic model there are two issues: delivery (vectors) and therapeutic genes (cytotoxic genes, prodrug activators, regulatory genes, replacement). One promising area is brain tumors -for a variety of practical reasons. He described studies with HSTK and ganciclovir. He is also exploring adenovirus vectors. Adenoviruses have the advantage of having greater cell free efficiency of infection. He is examining cytosine deaminase + 5-Fluorocytosine. Studies are also being conducted using a fusion gene expressing PF4 (a potent antiangiogenic molecule).
Dr. Okabe presented data on a PKC inhibitor, UCN-01, a fermentation product related to stauropsorine. This agent is a rather specific PKC inhibitor In preclinical studies, the greatest activity was noted in ras activated tumors. Moreover, combination with MMC or CDDP revealed synergism (but not with Doxorubicin, VP16). He also discussed Manumycin, a Farnesyl Transferase inhibitor, being developed by his company.
Dr. Oliff presented his studies of Famesyl transferase inhibition of malignancy as a model not of acute infectious disease but rather of chronic metabolic disease. An elegant series of experiments have demonstrated powerful effects on ras transformed tumors. At least one compound should be ready for testing in humans within the near future.

PARTICIPANTS

UNITED STATES

Dr. Allen Oliff
Merck Research Laboratories
16-101 WP
West Point., Pennsylvania 19486

Dr Mein-Chie Hung
M.D. Anderson Cancer Center
Box 79
1515 Holcomb Boulevard
Houston Texas 77030

Dr. H. Michael Shepard
Research and Development
Canji, Inc.
Suite 302
3030 Science Park Road
San Diego, California 92121

Dr. Martin Raber
M.D. Anderson Cancer Center
Box 92
1515 Holcomb Boulevard
Houston, Texas 77030-4009

Dr. Howard Fine
Dana Farber Cancer Institute
44 Binney Street
Boston Massachusetts 02115-3141

Dr. Michael Friedman
Associate Director
Cancer Therapy Evaluation Program
6130 Executive Boulevard, MSC 7438
Rockville, Maryland 20892-7438

JAPAN

Dr. Makoto Ogawa
Director, Aichi Cancer Center
1-1 Kanokoden Chikusa-ku, Nagoya 464

Dr. Takashi Tsuruo
Laboratory Research Department of Chemical Biology
Institute of Molecular and Cellular Bioscience
University of Tokyo
1-1-1 Yayoi-cho, Bunkyo-ku, Tokyo 162

Dr. Hideaki Mizoguchi
Department of Hematology
Tokyo Women’s Medical College
8-1 Hiraga-cho, Shinjyuku-ku, Tokyo 162

Dr. Mine Harada
IIed Department of Medicine
Osaka University, Medical School
1-5-2 Shikada-cho, Okayama 700

Dr. Fumimaro Takaku
President, National Medical Center
1-21-1 Toyama-cho, Shinjyuku-ku, Tokyo 162

Dr. Yutaka Ariyoshi
Chief, Department of Hematology
Aichi Cancer Center
1-1 Kanokoden Chikusa-ku, Nagoya 464

Dr. Michihiro Kuwano
Department of Biochemistry
Kyushu University School of Medicine
1-1-3 Umade Higashi-ku, Fukuoka 812

Dr. Michihiro Okabe
Kyowa Hakko Medical and Pharmacutical Institute
1188 Magaizumi-cho, Shinagawa-ku Tokyo 411