REPORTS ON SEMINARS

(1) Seminar on “Role of Cytokines in Cancer Treatment”
The first meeting of the FY88 U.S.-Japan cooperative cancer research program symposium on treatment was held in Tokyo on November 4 and 5, 1987. The topic was the “Role of Cytokines in Cancer Treatment”.
The first session dealt with Interferons (!!!and!!!especially). Dr. Ohno of Nagoya University began the discussion with a broad overview of IFN!!!. In renal cell cancer the aggregate Japanese data revealed 9 CR and 44 PR in 313 patients (14% responses). Doses ranged from 3-10 mu/day. In primary CNS tumors, 1 CR and 12 PR out of 121 patients were noted (11%). Responses were also noted in 13% of 38 patients with local therapy. For multiple myeloma, 1 CR and 32 PR in 181 patients were described (18%). There appeared to be a dose response relationship between dose and response (16 mu vs 7-8 mu, p <.01). Higher dose seemed more beneficial. For relapsed and refractory cases, the response rate was similar to that for previously untreated patients (22% and 20%). All types of myeloma responsed (lgG, lgA, BJ, K, !!!). In NEL, 13% responses were seen in 61 patients, but the precise histologies have not been defined. ATL in Southern Japan evidenced a 7/49 (14%) response rate. This effect was not dramatic and a combination trials is under way (especially the chronic form of ATL). MF patients responded (49% CR and 71% overall). Little or no activity was noted in breast (47), sarooma (28), colon (14), stomach (21), or hepatoma (17). In HCL 7/17 responsed, 4/14 CML, 3/19 CLL and 2/26 ANLL. The toxicities observed were similar to those described in the U.S. Pharmacologic data were also presented.
Dr. Foon (RPMI) presented complimentary overview from the U.S. data from 1 IFN a. He indicated that:

What is the optimal biologic dose for IFN a!!!? The MID for RIFN was 50mu/dx3/wk with dose reductions, For NHL (N=45), patients with low grade tumors were studied, and all had been pretreated. At NCI 13/24 (54%) and in U.S. 32/81 (40%) responses were noted For high grade tumors only 5/36 responses were reported. For CTCL, 9/22 responsed (3CR) and sometimes rather slowly. Patients with CLL, only 8/57 responses (~13%) were noted. In CML patients, 12/17 had hematologic CR (controls blood counts), and 6/14 had disappearance of Ph1 clone from marrow. However, no benefits yet observed in patients with blast crisis. For myeloma patients responses were seen but were quantitatively better for those previously untreated. In HCL, 9/95 and 37/95 PR were noted and most patients benefited from IFN therapy and the benefits persist. In HCL, most patients recovered NK activity as well as moncyte recovery. The IFN receptors (density) are equivalent for a responsive disease (HCL) and a resistant disease (CLL). He also described CLL cells treated with phorbol esters with results in HCL (excressences and TRAP +).
Dr. Ogawa presented the composite IFN!!!data from Japan. There are five RIFN!!!products in Japan and he presented data on two of these. A total of 31 evaluable patients were treated on Phase I studies with the Biogen product. Doses ranged from 2 to 64 mu/M² with 80% of patients experiencing fever and chills and 11% somnolence. Leukopenia was dose related and was sometimes dose limiting. In a broad Phase II study (6-12mu/m²) and 9/63 renal cancers (14%) had responses. Higher dose of IFN (40mu/M² either 3 or 5d/wk) resulted in 6/30 responses in RCC. In hematologic tumors, responses were noted in 2/17 myeloma. l/6 lymphoma, 7/43 CTCL. A second product was also tested (Genentech). Doses of 40mu/dx10 either IV or IM were tested. The toxicity of IM or IV therapy was rather similar to the previous trial. Leukopenia occured within 7-10 days and recovered promptly, and was dose related. Doses of 2-10mu/M² daily were the Phase II dosage. In Phase II studies, there was disappointing lack of response in RCC, GYN and NSCLC patients. Likewise in ANLL. myeloma or lymphomas, no results were noted. However. in MDS and CTCL response were noted.
Dr. Sachs presented the U.S. data for IFN!!!. He reviewed studies to determine the OID, to compare immunologic and pharmacologic endpoints, to determine optimal combinations and consider adjuvant trials. For Phase I studies many routes and schedules were employed. Quantitatively, the toxicity of IFN!!!were similar to IFN!!!, except that it caused hypertriglyceridemia (inhibiting lipoprotein lipase). T¹/2 is very brief with IV; with IM peak levels were achieved within 4-8 hours with larger AVC (similar to IFN!!!). The MTD is different for the Biogen vs Genentech products. Phase II activity was noted for CML (>20% PR) and minor activity in RCC, melanoma, HD, NPC, and CLL. This product was inactive in colon, sarcoma, myeloma, NHL, KS. Prelimary activity was noted in Waldenstrom’s and CTCL. In RCC, IFN!!!+ IFN!!!was not dramatically effective. To determine the optimal IFN!!!dosage, FC receptors in monocytes were studied and at 100mg seemed to decrease FC receptors). Similar data for HLA DR, H2O2 generation and NK activity were noted. An adjuvant study of 100mg/M²/d vs. observation will begin for high risk melanoma patiens after complete resection. He believes that IFN!!!affects NK activation, macrophage activation, HLA class II induction and FC receptors (ADCC). Combination studies will be studied combinations of IFN!!!+ IL2 (NK activation or TNF + IFN!!!are of high interest currently.
The second session dealth with IL-2 topics. Dr. Ogura of Tokushima University discussed LAK induction by IL-2. Blood from healthy individuals was obtained and lympocytes and macrophages (monocytes and lymphocytes increased LAK generation. Combinations of IFN!!!with IL-2 showed some antagonism, while IFN!!!seemed to promote LAK generation. Examining cytotoxic drugs + IL-2, MMC or Adriamycin or CDDP seemed to inhibit LAK generation. 5FU, Vindesine, VCR did not affect LAK appearance. One case of primary lung cancer (adenocarcinoma) was presented. Local instillation of LAK + IL2 intrapleurally decreased pleural effusion and cytology. The precise interaction of IL2 and cellular and humoral elements is still to be determined, but down regulation of LAK cells seems to be real, but the precise mechanism(s) are unknown.
Dr. Toge of Hiroshima University discussed LAK + IL2 studies in Japan. The rIL-2 was produced by Takeda Industries. A Phase I studies of IL2 alone studied daily IV infusion (1 hour) for five consecutive days. Pharmacology studies were performed. Fever was the DLT and MTD was 1,000u/d. The Phase II studies consisted of 157 patients at 47 institutions. PRs were seen in 2/28 gastric, 2/23 H + N, 1/13 lung and 1/7 breast cancer patient. Local instillation was responsible for 17/48 skin and 3/14 H + N cancer patients. Fever (55%) and eosinophilia (22%) were the most common side effect.
Data on adoptive therapy with LAK + IL2 were also presented. LAK cells were generated by leukopheresis, these cells incubated for 3-7 days (+ IL2 x 3-5/week). Patients receive 10⁹ cells as single dosage. A total of 97 patients were evaluated. Patients received l-37 treatments and 2x10⁷ to 8x10¹⁰ cells. Data are very preliminary but responses were noted in CNS, RCC, and ALL. He also presented preliminary data with plasma excharge plus LAK + IL2.
The data from the U.S. studies of LAK + IL2 were presented by Dr. Coltman of SWOG. The protocol of the NCI was utilized for LAK generation for the extramural studies (5 days of IL2, 2 of rest, apheresis for 5 days, IL2 + LAK cells are then reinfused). A total of 6 institutions participated in these studies for patients with RCC and melanoma. A total of 35 RCC patients were entered and of 33 evaluable (71% nephrectomy) the major toxicities were hyptension (73%), weight gain (56%), creatinine elevation (31%), MI (2%), and CNS toxicity in 20-30%. Hepatitis contamination of plasma was also a significant problem. A mean dose of 13IL2 doses, 7x10¹⁰ LAK cells infused and 10 IL2 + LAK doses were utilized. These doses were similar to those prescribed by Rosenberg. Of 32 evaluable patients there were 2 CR and 3 PR. The NCI described 4/36 CR and 8/36 PR. For melanoma patients, 1 CR and 5 PR in 32 patients were noted. For colon cancer 1/21 CR and 2/21 PR were noted. These extramural trials suggest that responses seen at NCI could be confirmed and elements of this technology transferred.
Dr. Tamura of the National Cancer Institute presented data on IL2 + IFN. He performed a phase I study of IL2 alone initially. Three schedules were utilized: 2 hour IV x 5d, 24 hour CIx28d, and 24 hour CIx5d q 4 weeks. Doses varied from 3.3.x 10⁵ to 2.2x10⁶ u/ M²/day. A total of 34 patients were studies. Fever, malaise, nausea and vomiting were most frequently observed with hypotension and renal insufficiently being DLT. Serum pharmacokinetics were defined for various two hour infusions, and for the GI schedules. Preclinical data on rIFN + IL2 demonstrated dramatic improvements on survival. Hence a Phase I study was initiated. Twenty-six patients were evaluated (19 had ECOG PS l). IL2 was given for 24h CI x 5d q 4 weeks with rIFN!!!daily x 5/7. Both agents were escalated, the MTD 1.1 x 10⁶ u/ M² IL2 +6x 10⁶ IU/M² of rIFN. No objective responses were noted in 23 patients. The number of cells with IL2 receptors increased with combined therapy, while leu 7 and 11 decreased. OKT8 slightly decreased while OKT4 slightly increased.
Dr. Mehich then presented his data with immunomodulation by chemotherapy (specifically Adriamycin). Adm has been shown to augment macrophage differentiation, inhibit NK (spleen) and augment N K (PEC). In mice, ADM x 5d will demonstrate immunomodulation of the host. Studies of Adm + IL2 (+ LAK) have also been initiated. If Adm was given to the recipient animal prior to IL2 + LAK, some synergy was observed. Adm + TNF also demonstrates some increased benefits. Clearly Adm has immunomodulation and this may have therapeutic import. Other drugs will be explored in this manner.
The next topic discussed was TNF, initiated by Dr. Niitsu of Sapporo University. TNF has a very wide range of interactions with cytokine network, inflammation and immune reactions (IL2, IFN, CSF, PGE2, etc). Mechanisms of antitumor effects include direct cytotoxicity, cytostasis (C-myc), immune (mac) activation and vessel necrosis. In vitro tests reveal high metastatic and low metastatic clones of Meth A induced fibrosarcoma with different sensitivity to TNF and possessing dissimilar numbers of TNF receptors. There is a constant recycling of TNF receptor (4:1::internal:surface) and the lysosome is the site of degradation. DMSO, NaAzide, NaF reduced sensitivity to TNF by interfering with lysosomal activity or -OH generation. Normal embryonic cell lines and PHA stimulated lymphocytes have TNF receptors but show no cytotoxicity. Both normal and tumor cells internalize the TNF receptors. Clinical studies of local administration of TNF demonstrate 3/7 regression (Breast is only true PR). Clinical benefits were also noted in myeloma and CML in blast crisis. The delemmas of TNF are toxicity (chills, fever, malaise. anorexia, hypotension) and clinical resistance. Recently Ketoproten (NSAI) prophylaxi reduced hypotension and fever. Ketoproten does not diminish cures in murine tumor models. TNF resistance may be related to m-RNA abnormalities and the generation of a TNF-like molecule. Normal cells and TNF resistant tumors make endogenous TNF-like substance. Synergism with several cytotoxic drugs has been demonstrated including Adm, ActinoD, MMC, AraC, CDDP, Cytoxan, etc. Likewise hyperthermai and TNF are synergistic.
Dr. Sachs provided an overview of U.S. clinical TNF data. Beginning in 1985, Phase I studies began in the U.S. Both single and multiple dose trials were initiated. No antibodies to TNF have been detected in more than 300 cases. For short IV injections the DLT was hypotension (some marrow suppression noted), For IM or CI, cytopenias and local inflammation noteworthy. Mild increases in triglycerides were noted (since TNF is identical with cachenctin). Mild hepatotoxicity was noted but this was not clinically relevant. The CI route also produces CNS toxicity. apparently similar to TIA’s, and seizures (lowering seizure treshold). Additionally, a subtle pulmonary toxicity is also produced by TNF (10-15%, decrease in DLCO) but this is clinically inapparent. Hence patients with CNS metastases or severe pulmonary dysfunction are excluded from study.
Clinically, the overall response rat is low but some responses have been observed in gastrointestinal adenocarcinoma. Studies of TNF + IFN are underway.
Dr. Kataoka next presented his studies of IFN + Chemotherapy (CT). He proposed that CT results in greater tumor cell killing while IFN modulates host immunology. IFN induces membrane changes (decreased fluidity and increase microfilaments) and metabolic changes (decrease DNA and protein synthesis, increase CAMP, PGT<and 2’f’A), Specific data on IFN!!!+ Colchincine or Cytochalasin D demonstrated synergy with H.Ep#2 cell lines. Studies of IFN!!!+ VCR had similar results, but 6MP resulted in antagonism. Aslo HLBI + MMC was effective for gastric cancer cell lines. This combination was schedule dependent. Simultaneous administration was not as effective “as sandwich therapy”.
A very interesting case of ATL (chronic phase) responsive to Cytoxan + IFN was presented. This patient had been refractory to cytoxan alone.
Dr. Friedman reviewed the ongoing studies in the U.S. of IFN + CT. Large pivotal trials are ongoing with IFN!!!+ CT. Crucial issues of dose ratios. timing and schedule have not been adequately defined for either preclinical or clinical studies. Most interesting studies are ongoing with four trials in myeloma, two in CLL, nine in NHL and 2 in HCL. Issues of induction of CR. maintenance in CR, and for those with resistant disease. Particular attention to clinical situations where both CT and IFN are effective will predominate, Data from these trials will be available in 1 to 3 years.

(2) Seminar on “New Screaming System and New Drugs”
The second U.S.-Japan Joint Scientific Seminar on New Agent Development was held February 5 and 6, 1988 in Kauai. Hawaii, The first presentation was by Dr. Baker who described a new screening system utilized at his institution. Utilizing a murine or human solid tumor system, in vitro analysis of drug impregnated paper discs detect solid-tumor active drugs. The tumors examined are L1210, 03 pancreatic. C38 colon. H-125 lung. and CX-1 human colon cancer. Therefore, lung, pancreas and colon cancers are primary targets. After screening 10,000 compounds, <1% are so]id tumor selective and 6% are leukemic selective. An example is Flavone Acetic Acid (FAA). which is active against solid tumors; less so against leukemias. Unfortunately. it is not very potent and has a narrow therapeutic index. New analogues of FAA appear to be quite promising, Other interesting agents are GO 1734, Batracylin, Acetoxyhexamide and Acivicin. Continued efforts are being made to determine whether human cell lines are more predictive than murine lines. These investigators will continue random screening of novel agents which lead to analogue searches.
Dr. Tsukagoshi next presented the new screening systems under development in Japan. Overall, some 400 synthetics and 44 natural products were tested in his institute. Nude mice implanted with human gastric cancer are being evaluated. A new system being evaluated is based on Src integration and activation at 33° but inactive at 39°. Oxanosine was selected by this system; it inhibits IMP dehydrogenase which decreases GTP and GDP (which are cofactors of rat gene product P21). A third new system examines tumors growing on chorioallantoic membrane. New information should be provided in the near future.
The status of’ New Platinum analogues in the U.S. was reviewed by Dr. Rozencweig. He began by outlining the need for new analogues. The evaluation of CBCDA reveals that there is less gastrointestinal, neurotoxicity and nephrotoxicity than cis-DDP. There is however more hematologic toxicity. Activity has been identified for ovarian cancer patients. For those responding to cisDDP, 26% respond to CBDCA; in those refractory the PR rate is about 5%. For head and neck cancer activity is also noted. Major randomized trials of CBDCA + Cytoxan vCisDDP + Cytoxan are ongoing. Relatively more thrombocytopenia than leukepenia is noted. The NCIC and SWOG comparison studies have not indicated any differences for ovarian cancer patients. Other diseases of interest include head and neck and SCLC in combination.
New platium analogues in Japan were reviewed by Dr. Ota. Of interest DWA 2114R, NK 121, and 254-S may be superior to CDDP in terms of therapeutic index. Clinical data with 254-S is available and a Phase I study completed; leukopenia and thrombocytopenia were evident. Also, DWA 2114R was studied in a Phase I manner. Similar WBC toxicity was noted as close-limiting. The protein binding of 254S is much less than that for CDDR. Several Phase II studies are ongoing at this time.
Dr. Gabrilove discussed her work with GCSF (uniquely stimulating neutrophiles). GMCSF stimulates all granulocytes and monocytes. GCSF affects GM-CFU progenitors. There are, of course, many types of neutropenia, but one exciting area is in iatrogenic chemotherapy induced leukopenia. One initial study examined bladder cancer patients with MVAC chemotherapy. GCSF was initiated 12 days prior to MVAC and then again 4 days after the first MVAC. For the pre MVAC portion of the study - 22 patients demonstrated a dose dependent increase in neutrophiles up to 60-100Mgm/Kgdosage. No changes were noted in red cell or platelet profiles. Toxicity was mild except for medullary bone pain especially in sternum, back and hips (by IV infusion).
For 18 patients receiving GCSF after MVAC, there is a dose dependent biphasic increase in neutophiles. The absolute number of days with leukopenia is much smaller with GCSF and adequacy of therapy is better with CSF administration. Interestingly. there was less MVAC induced mucositis.
Dr. Takaku provided complimentary data from Japan with a GCSF product. In normal volunteers the pharmacology and physiology of this agent was defined. Increases in CFU-E, BFU-E, CFU-Meg and CFU-GEMM were observed in two normal individuals given rh-GCSF. Some increases in GCSF were noted in patients receiving allogeneic BMT (as well as some patients with CML, etc.). Testing in various forms of anemia, myelodysplasia and AIDS patients is ongoing. Studies of the potential stimulation of leukemic cells by GCSF seem to indicate a dose difference (low dose stimulate normal while high doses stimulate leukemic marrows).
The next presentation concerned the value of pharmacology studies in Phase I activities. The distinction between pharmacokinetics and pharmacodynamics (toxicity) was made. Specific data on CBDCA was presented. This drug has slow protein binding and high urinary clearance. Nomograms could be constructed to describe the pharmacodynamics of CBDCA in patients with renal insufficiency. By examining the percentage of change in platelet count and the AUC and using simple algebra, formulas for dosage of CBDCA necessary to achieve a desired platelet nadir could be derived. These predictions proved excellent. Corroborating data utilizing Menogaril also were provided. Finally, H M BA is being studied utilizing these sorts of considerations.
Dr. Umezawa then presented studies with FAD-104, a new semi-synthetic anthracycline. This agent has a Fluorine atom at the 2’position to stabilize the attached ring structure. FAD-104 is more stable than Daunomycin. Moreover, FAD-104 has better murine antitumor activity. It appears to have little mutagenicity (as indeed by the Salmonella assay) and has avid binding to DNA. Further testing is ongoing with this agent.
Dr. Tsuruo described another new anthracycline, KRN-8602 which may be less susceptible to multidrug resistant P-glycoprotein. This agent is effective against P388 both po and pr. It has similar IV effectiveness as Adriamycin. It is active against P388 or L1210 resistant lines (ADM,VCR, MMC).
The second day Dr. Ogawa began by reviewing new antibiotics in Japan. Phase I studies are ongoing with KRN8602, Libromycin (a Bleo analog), Deoxyspergualin, FK973. In Phase II, SM5887 (an Anthracycline) is nearly completed.
Libromycin is a Bleo analog with reasonable murine antitumor activity (L1210, P388, B16, etc). Pulmonary toxicity is much milder than Bleo but myelotoxicity was much more evident. Major toxicity included gastrointestinal, fever, fatigue, alopecia, leukopenia, thrombocytopenia.
Deoxyspergualin is L1210, P388, C1498 active; and was schedule dependent. Immunologic effects were also postulated. Major toxicities included GI, hematologic neurologic and cardiovascular. Mild toxicities have been observed in this on ongoing Phase I study.
The phase I study of SM5887 was completed - 19 patients and 30 courses. A total dosage of 130mg/m²/course was achieved. Leukopenia and thrombocytopenia were dose limiting at 100mg/m² q 3 weeks. Pharmacology studies are being performed.
Dr. Taguchi described a new analogue of Camptothecin (called CPT-11), which was selected to provide less toxicity and better efficacy. Active against both murine and transplanted human xenografts, CPT-11 was active against VCR or ADM resistant P388. A Phase I trial was initiated in October of 1987, 18 patients have been evaluated. The major toxicity of note is leukopenia occurring about 7 days therapy and recovering in 14 days.
Dr. Sobel described the work proceeding with antimetastatic agents. The basement membrane surrounding a tumor mass is a key feature (laminin, proteoglycan, type IV collagen). Laminin receptors are present in malignant cells in a greater number than in benign cells. More metastatic potential was noted in those cells with more laminin receptors. The anaplastic, infiltrating tumors had more receptors.
Studies of liposomes coated with laminin receptors have been conducted. Cell killing with ADR encapsulated liposomes is observed with highly metastatic cell lines.
Dr. Sobel also has developed a probe to detect metastatic potential and to exploit these findings. Finally, his group is defining motility factors for the malignant of tumor cells, (Autocrine motility factor). AMF increases chemotaxis toward laminin, etc. and it is somewhat nonspecific.
Dr. Tsuruo discussed uses of agents to reduce R-glycoproteing associated drug resistance. In attempting to define antimetastatic agents, multiple clones of colon 26 cell line were isolated. Correlations with platelet aggregating ability were made, and an inhibitor (20Al l) was tested.

(3) SEMINAR ON “CURRENT PROGRESS IN COMBINED MODALITIES”
The U.S.-Japan Cooperative Research Program Meeting was held March 14-16, 1988 at the Nikko Hotel in San Francisco, California. The meeting represented a broad spectrum of radiation oncologists and medical oncologists and addressed the subject of “Current Progress in Combined Modalities”. It covered two and half days and addressed the major scientific areas of hyperthermia and radiation, chemical radiation sensitizers, radiotherapy and chemotherapy, particle radiotherapy, three-dimensional treatment planning and intraoperative radiotherapy.
The first session was chaired by Drs. Dewey and Tanaka and addressed hyperthermia in radiotherapy and combined modalities. William Dewey, Ph.D. spoke on advances in thermal biology and thermal dose concepts. He pointed out that the maximum interaction of heat and radiation occurs when the two are given simultaneously. He addressed the issues of the therapeutic ratio and the influence of tumor and normal tissue and thermal enhancement ratios on this factor. He also addressed the questions of uniform thermal dose and the current problems with agreeing on such a unit.
Gloria Li, Ph.D. then spoke on heat shock proteins as an indicator of thermotolerance and its clinical relevance. She pointed out that the concentration of HSP 70 appears to correlate best with heat resistance. She found that a cell’s ability to reinitiate heatshock protein (HSP) 70 synthesis inversely correlated with retained thermotolerance. Therefore, the determination of the rate of reinduction of HSP 70 may be a rapid measure of retained thermotolerance. She also discussed a double antibody sandwich ELISA assay for HSP 70, This assay is proposed as a clinically relevant and practical method to predict thermal response.
George Hahn, Ph.D. then spoke on cross resistance between hyperthermia and chemotherapeutic Drugs. He pointed out that thermotolerance can be induced by a variety of drugs including agents which induce HSP’s. In addition, partial thermotolerance can be induced by dimethylsulfoxide and steroid hormones without the induction of HSP. Thermotolerance modifies the responsiveness to adriamycin, bleomycin, actinomycin D, and cisplatinum. For BCNU, cytotoxicity is not modified at pH 7.4 but is at lower pH. The results suggest that more than one common mechanism is responsible for induced drug resistance.
Yoshimasa Tanaka, M.D. presented a paper on effects of hyperthermia and intra-arterial embolization with starch microspheres. He reported on the anti-cancer effects of the combination of embolization and hyperthermia. They found that this procedure reduced blood flow in tumor and normal tissue. With decrease in blood flow increases in temperature and decreases in pH were greater in the tumor than in muscle. A similar procedure was tried in patients with liver cancer and temperatures 1-3°C higher were achieved after embolization.
Peter Fessenden, Ph. D. then described developments in microwave surface applicators for hyperthermia. He described his work in developing spiral microstrip applicators and in applying such applicators with a scanning device to uniformly heat superficially over a large area. They are also exploring an array of multiple tightly packed spiral antennas.
Yasumasa Nishimura, M.D. then reported on radiofrequency capacitive hyperthermia combined with radiotherapy for the treatment of abdominal and pelvic tumors. 33 patients were treated regionally once per week using the thermotron RF-8. They reported that an average temperature of more than 42°C was achieved in the center of 20 of 33 tumors. An intratumoral temperature of 42°C or greater could be maintained more than 20 minutes in 54% of the lesions. They feel that his device is at least as good as the annular phased array as a regional heating unit.
Paul Stauffer, M.Sc. then reported on his work in developing interstitial heating modalities. He described three major types of heating using implantable microwave antennas, radiofrequency electrodes and ferromagnetic seeds. Each of these methods appear capable of heating relatively uniformly over significant volumes so long as they can be adequately implanted with appropriate intercatheter distances.
Mitsuyuki Abe, M.D. then reported on RF capacitive heating in the treatment of cancer. In his general review of sites throughout the body, he reported on the tumor center temperatures and has found that a temperature of greater than 43°C could be achieved in 60-75% of head and neck, thorax and upper abdominal tumors, however only 21% m the upper abdomen and 50% in the lower extremities were heated to this level. The temperature achieved was also related to the thickness of the subcutaneous fat with poor results being attained with thickness greater than 15mm. Complete response in tumors were greater for superficial and subsurface lesions at 68 and 54% where as they were lower for deep tumors (23%).
Sunao Egawa, M.D, then reported on results of multi-institutional controlled trials for the evaluation of the effect of combined therapy with radiation and hyperthermia to superficial tumors. This was the report of a multi-institutional study which employed radiation of 2 Gy per fraction, 5 fractions per week to 50-70 Gy. Superficial hyperthermia was used once per week for at least 40 minutes and at least more than 42.5°C. Patients were randomized to receive hyperthermia and radiotherapy or radiotherapy alone. Ninety-two patients were evaluated. The complete response rate was 45.5% in the combined treatment group and 37.5% with radiation only. The CR + PR rate was 81.8 for the combination and 62.5 for radiotherapy only. This difference was statistically significant (P<.05).
After a lunch break, Malcom Bagshaw, M.D. presented the Stanford experience with clinical hyperthermia. He particular concentrated on their experience in the Phase I evaluation of equipment for hyperthermia in the treatment of cancer. A total of 21 irradiative electromagnetic ultrasound and interstitial applicators and three types of thermometry systems were extensively tested at Stanford. A total of 996 treatments involving 268 separate treatment fields and 131 patients was performed. He concluded that the heating ability of a variety of devices was not optimal. Among these, the microwave microstrip devices seem to give the most even heating for large areas in the superficial range. Deep heating was limited by pain and uneven heating with numerous cold spots. Thermometry was found satisfactory with the advanced type BSD Bowman and third generation Luxtron systems.
RF capacitive heating combined with radiation in cancer treatment was reported by Yasuto Onoyama, M.D. from the Osaka City University Hospital. He concluded that the results of his clinical study of RF capacitive hyperthermia were encouraging for both shallow tumors and deeply seated tumors. He observed a high response rate in radio-resistant non-epithelial tumors in particular.
Eizo Yabumoto, M.D. then presented data on clinical experiences with RF-interstitial hyperthermia combined with external radiotherapy from Shiga University. He concluded that interstitial hyperthermia is superior to external heat techniques because of better heat distribution in the tumor and sparing of normal tissue. He points out that it is useful even with external radiotherapy and not necessary with interstitial irradiation. The result with combined electron beam radiation and interstitial heating was excellent with horizontal implants, 5 or 6 patients achieving complete response.
The March 16th session concluded with a discussion of chemical sensitizers chaired by Drs. Mori and Phillips. The first paper by Tsutomu Kagiya, Ph.D. discussed an advanced radiosensitization system, combining nitroimidazole and Chinese herbal medicine. They found that both the administration of nitroimidazole hypoxic sensitizers and daily administration of herb extract 912 has some effect. After irradiation, it showed enhancement of effect in vitro and in vivo. The combined effect gave increased enhancement. A second series of studies evaluated a fluorinated nitroimidazole, KU-2285, which demonstrated high radiosensitization. in particular when combined with hyperthermia.
Martin Brown, Ph.D. discussed the synthesis and testing of new sensitizers and hypoxia specific bioreductive drugs. He reviewed the development of SR 2508 as the optimal 2-nitroimidazole. He pointed out that nitroimidazoles with greater electron affinity than misonidazole were superior in vitro but not in vivo. Effective strategies appear to be targeting radiosensitizer to DNA through use of weekly basic compounds. such as RO O38799 or DNA binding compounds. Other classes of compounds which produce sensitization in vivo but not in vitro such as nicotinamide have been found and are thought to work through changes in blood flow. Another promising approach is the development of hypoxic cells cytotoxins, such as SR 4233. This and other bioreductive cytotoxic compounds have the potential, in combination with blood flow manipulation, of killing large percentages of total tumors cells.
Tomoyuki Mori, M.D. then presented data on new possible hypoxic cell radiosensitizers. He described the formation of a cooperative research group which is developing sensitizers in Japan. This group is partially supported by the Japanese Ministry of Education, Science and Culture. They have set up a very elegant system, similar in many respect to that used by the National Cancer Institute in Drug Development. It utilizes EMT6 sarcoma cells, SCCVII tumors and Chinese hamster V79 cells. They have discovered a number of interesting compounds, on one of which is at least as good as SR 2508. The group felt that this effort would probably lead to exciting new compounds for clinical trial.
Sei-ichi Nishimoto, Ph.D. presented information on the molecular design of nitroimidazole derivatives as hypoxic sensitizers. He particularly emphasized the importance of tumor affinity in developing and proving synthesizers. He found that the concentration in tumor of a nitroimidazole was proportional to the tumor affinity factor. Novel types of fluorinated nitroimidazoles possess higher tumor affinity resulting in higher SER. There was general enthusiasm among the participants during the discussion and round table. It was felt that several leads to the development of new classes of compounds were present and that in the future we should look for interesting clinical trials with fluorinated compounds and with hypoxic cell cytotoxins.
On the second day of the symposium, March 15, 1988, the session on radiosensitizers continued with a series of reports on clinical trials. Todd Wasserman, M. D. reported on RTOG sensitizers trials. He reviewed the Phase I pharmacology data that had been obtained on misonidazole, des-methylmisonidazole, and SR 2508 and reviewed the rationale for introducing drugs subsequent to misonidazole. He pointed out the current studies with SR 2508 and the current emphasis on evaluation in head and neck cancer in the RTOG and in separate trials in Europe. He emphasized the strategy of the RTOG in looking for and developing new compounds, conducting Phase I and Phase II testing and then definitive randomized Phase III trials. Although they were not positive for misonidazole, they were very successfuly conducted and clearly evaluated the drug. Now that agents with five times better advocacy or present, it is hope that positive studies will evolve.
Norman Coleman. M.D. reported on a development of clinical trials with SR 2508 (Etanidazole). Dr. Brown pointed out that SR 2508 gives the same radiosensitization as misonidazole but with far less toxicity. A dose of 2gm/m may now be given with greater than or equal to 17 radiotherapy treatment. He reviewed the current trials using SR 2508 with fractionated radiotherapy which included a Phase III head and neck cancer trial, Phase II trials in prostate. esophageal and bladder cancer and a Phase I evaluation of SR 2508 plus Ro-03-8799 being conducted in the United Kingdom. Other studies included continuous infusion SR 2508 with brachyterapy and evaluation of SR 2508 as a chemomodifier and for intraoperative radiation.
Victor Levin, M.D. then reported the NCOG randomi7.ed trial of BUDR and malignant gliomas. He reported on 250 patients who had been assigned to receive BUDR as a 800mg/m per day, 4 days per week infusion each week for 6 weeks of radiotherapy. Of 230 patients, they have had pathologic review, 116 were glioblastoma and 114 anaplastic astrocytoma. A major toxicity was cutaneous with one patient developing a fatal Steven’s Johnson syndrome. No Grade 4 hematologic toxicities occurred. Medium time to progression was 86 weeks for non-glioblastomas and 29 for glioblastoma multiforme. This study is continuing as one arm of a randomized trial in which half the patients receive this therapy and half receive a brachytherapy implant boost.
All speakers then discussed the current status of hypoxic cell sensitizers. It was agreed that closer cooperation between U.S. and Japan in developing hew drugs would be very important. The joint effort in Japan appears to be capable of identifying exciting new compounds and in the future joint clinical trials could be advantageous.
The next session was then chaired by Drs. Egawa and Friedman and addressed the question of combined radiotherapy and chemotherapy. Eric Hall, M.D. initiated the discussion with a presentation on oncogenic transformation by radiation and chemicals. He pointed out the advantage of in vitro assays of oncogenic transformation because of their ability to make quantitative assessment at the cellular level of oncogenic potential of physical, chemical and viral agents. Some agents such as benzopyrene produce much higher incidences of transformation for a given level of cell kill than other agents. A number of agents have been found to enhance or suppress the incidence of transformation. These include tumor promoting agents, superoxide dismutase and a variety of retinoids which can inhibit cell transformation.
Michael Friedman. M.D. then reviewed the status of combined modality studies in la bowel cancer. He pointed out the very interesting results of a serious of studies of adjuvant therapy in rectal cancer. It appears that disease free survival is definitely enhanced by the combination of radiotherapy and chemotherapy with 5-fluorouracil and mitomycin C. The combination is superior to radiotherapy alone or chemotherapy alone with advantage both in disease free and overall survival. Radiotherapy alone as an adjuvant does not appear of major advantage in terms of survival although it does reduce local recurrence. A number of combined modality studies are being proposed including radiation with 5-fluorouracil and folinic acid, radiation with multi-drug chemotherapy and radiation with high dose 5-fluorouracil.
Norman Coleman, M.D. then discussed the perspectives on cross resistance between radiotherapy and chemotherapy. He pointed out that there are some theories which show there is a negative interaction possible between radiation and chemotherapy when they are given simultaneous and that optimal treatment might be with remote administrations of two very effective agents. On the other hand, other trials have shown advantage for simultaneous treatments. He pointed out that radiation rarely induces chemotherapy resistance but that resistant populations can occur within tumors. Drug exposure can clearly cause resistance Mechanisms for cross resistance or concomitant resistance between radiotherapy and chemotherapy include pharmacologic effects of radiotherapy on chemotherapy, physiologic effects such as nutrient depletion, biochemical perturbations with fluctuations in substances such as glutathione and repair. Finally gene expression through amplification or oncogene expression could cause alteration in sensitivity to the other agent.
Robert Kallman, M.D. then presented work using experimental mouse tumor and normal tissue systems that indicated a significant advantage to the combination of radiation and cisplatinum, when given as a fractionated course.
Tomohiko Okawa, M.D. then discussed the efficacy of radiotherapy combined with intra-arterial infusion in advanced head and neck cancers. He described 70 patients with carcinoma of the maxillary sinus treated with radiation and surgery with or without chemotherapy. In this series of patients treated sequentially, the first group was treated with radiotherapy alone, to 60 Gy, the second group to 50 Gy with 5-fluorouracil, and the third group to 40 Gy in four weeks with adriamycion. There was an improvement in survival from 13% to 54% from the first to the third group and a similar improvement in local control.
In a subsequent talk, Karen Fu, M.D. reported on the results of combined bleomycin and radiotherapy for advanced head and neck cancer in a randomized trial conducted between 1978 to 1984 The Northern California Oncology Group showed a significant benefit for the combination of radiation and chemotherapyu as compared to radiation alone for a group made up essentially of stage IV squamous cell carcinomas. Complete response rate, disease free survival and overall survival were all improved. There was some increase in acute reaction and in late reaction, although the later were not statistically significant.
The next presentation by Timothy Kinsella, M.D. discussed radiation therapy and chemotherapy in soft tissue sarcomas. He pointed out the advantages of chemotherapy In several series of patients treated with radiation for retroperitoneal tumors, pelvic sarcomas and for high risk sarcomas in children and young adults. Chemotherapy used in retroperitoneal tumors showed some improvement in local control but did not cause any difference in overall survival. A very aggressive combination of radiotherapy and chemotherapy for pelvic sarcomas yielded complete remission in 22 to 23 patients with permanent local control achieved in all 23, 9 systemic relapses have occurred. Dr. Kinsella’s general conclusion was that aggressive multiple-modal therapy does show an advantage in the highly anaplastic sarcomas and in particular, in the younger patients.
The next presentation by Hiroshi Tsujii, M.D. discussed improved results of treatment in nasopharyngeal carcinoma with combined radiotherapy and chemotherapy. A total of 77 patients with squamous cell carcinoma were treated by 3 different methods. Prior to 1983 patients were treated with radiation alone and subsequently with chemotherapy consisting of cyclophosphamide, methotrexate and fluorouracil. The addition of chemotherapy was effective with prolonged survival rates and reduced relapse rates.
The session on radiotherapy/chemotherapy concluded with a discussion of recombinant human granulocyte colony stimulating factor in cancer patients at risk for chemotherapy induced neutropenia by Akihiro Shimosaka, Ph.D. These studies suggest that RhG-CSF will increase the number of neutrophils in patients with neutropenia due to any cause such as chemotherapy, radiation or other causes if they are cell responsive to RhG-CSF. The human granulocyte colony stimulating factor used was from a human bladder cell line, cloned and expressed in E. Coli.
In a round table discussion, there was general agreement among the participants that combined radiotherapy and chemotherapy was an important modality. We appear now to better understand its enhancement of normal tissue injury and a number of combinations have been found which can be given simultaneous with radiation with improved results and only modest increases in toxicity. Although combinations with certain agents such as actinomycin and perhaps adriamycin do not seem to enhance the therapeutic ratio, other agents such as 5-nuorouracil, cisplatinum, mitomycin and bleomycin do seem to enhance this ratio.
The final session on the second day was devoted to a review of high LET and particle radiotherapy. It was chaired by Drs. Joseph Castro and H. Tsunemoto. The first speaker was Eleanor Blakely, Ph.D. who discussed the potential for combining high LET therapy with sensitizers and chemotherapy. She described particles being studied with human cells in vitro evaluating interactions with SR 2508, IUDR and cisplatinum. Because of the mixture of low and high LET events in charged particle beams, modification can be seen with these agents over the full range of clinical spread beams. Thus, there is a potential to improve results with charged particles as with low LET photons using chemical modifiers although the enhancement ratios are not as large.
Hiroshi Tsunemoto, M.D. then discussed particle radiation therapy at the National Institute for Radiologic Sciences in Japan. He first reviewed the clinical trials with fast neutrons performed at NIRS using 30 MeV deuterons on Beryllium. A total of 1623 patients were treated between 1975 and 1987. Major sites included head and neck, lung, brain, melanoma and osteosarcoma. They concluded that results were improved in patients with tumors of the salivary glands, pancoast tumor of the lung, osteosarcoma, soft tissue sarcoma and malignant melanoma. Results were not improved over conventional radiotherapy for glioblastoma multiforme, head and neck, esophagus and prostate. He then described the proton therapy at NIRS with 70 MeV protons penetrating up to 36mm. Forty-four patients have been treated, of whom 79% achieved local control. Plans at NIRS now call for the construction of a new accelerator capable accelerating helium to silicon and even argon with a maximum energy of 800 MeV/amu. Three treatment rooms are planned and the machine is scheduled for completion in 1993.
Takashi Nakano, M.D. then reported on proton therapy for occular melanomas at NIRS. 12 patients with ocular melanoma were treated between 1985 and 1987. The treatment technique was described and the results reviewed. Two of the 12 patients have required enucleation because of blindness and glaucoma.
The next presentation by Joseph Castro, M.D. reviewed the experience at Lawrence Berkeley Laboratory in treatment with charged particles including helium, carbon, neon, silicon, and argon ions. Over 1,000 patients have been evaluated and improved dose localization has been found with helium as well as enhanced biological effectiveness with neon, silicon and argon. A series of Phase II studies were carried out with particular emphasis on helium and neon. In general, all of the major body sites were covered from this work. It was evident that favorable results were obtained with paraspinous and base of skull chordomas and chondrosarcomas with 74% local control. The treatment of 207 uveal melanoma patients resulted in only 9 local failures. Rather extensive trials in carcinoma of the esophagus and carcinoma of the pancreas did not reveal any advantage with charged particles over conventional photon therapy. Trends toward possible advantage however with neon were seen with glioblastoma multiforme, paranasal sinuses, salivary gland, lung, prostate and sarcoma patients. Currently, clinical trials are continuing in these encouraging areas.
Toshio Kitagawa, M.D. discussed proton radiotherapy at the Particle Radiation Medical Science Center of Tsukuba University. Studies have been underway since April 1985 and 75 patients with locally advanced lesions were treated. Radiation was given with 200 MeV proton beams oriented either vertically or horizontally. Doses between 70 and 90 Gy were given to 60 patients who have more than 8 months follow-up and evidence of local control of 73%. These results are very encouraging and clinical trials will be expanded.
Thomas Griffin, M.D. then reported on an overview of the United States Neutron Therapy Program. He reviewed the initial studies carried out at the physics based units with encouraging results particularly in cervical lymph nodes, salivary gland carcinomas and carcinoma of the prostate. Subsequently, three hospital based dedicated neutron machines have been installed at the University of Washington, UCLA and MD Anderson Hospital and joint clinical trials are underway. These are evaluated in a randomized fashion. Trials are in tumors of the salivary gland, lung, prostate and head and neck. The salivary studies have already been closed because of a tremendous advantage of neutrons over photons.
The round table discussion emphasized the importance of continued particle studies with particular emphasis on delineating those sites in which neutrons are advantageous in addition to carcinoma of the salivary gland. It was felt that charged particle studies are highly important because of the encouraging results at certain sites. The participants were enthusiastic about the prospect of second heavy particle accelerator in the world to be located at Chiba in Japan and by the effectiveness of protons at Tsukuba. Thus, future prospects exist for cooperative trails between the Harvard Cyclotron and Tsukuba and between Berkely and NIRS at Chiba.
The third day of the meeting commenced with a session evaluating three-dimensional treatment planning. The session was chaired by Drs. Ling and Tsujii.
Gerald Hanks, M.D. first discussed the recently completed National Cancer Institute sponsored evaluation of 3-D treatment planning for photon beams with particular emphasis on the results at the University of Pennsylvania. He particularly emphasized a study of the role of three-dimensional treatment planning in carcinoma of the larynx at the four institutions participating in the contract. A total of 30 different treatment approaches were devised for 2 patients with larynx cancer. They found that three-dimensional treatment planning was of potential value in optimizing treatment of the larynx cancer with improved target coverage and novel beam arrangements possible with beam’s eye view. He also reported on results with carcinoma of the breast which evaluated 38 treatment plans. These studies revealed that higher energy photons of 10 MeV and greater were associated with an unacceptable target coverage at shallow depth. These studies revealed 6 MeV beams were the energy of choice for the intact breast. Three-dimensional derived plans improved slightly on standard plans.
Benedick Fraass, M.D. then discussed an overview of a clinical 3-D treatment planning system. the University of Michigan Plan. He reviewed this very exciting system which employs standard image formats as well as three-dimensional surface descriptions. In this system, three-dimensional calculations and three-dimensional display allows a complete description of the tumor in normal anatomy, as well as their precise relationship. It incorporates MRI, as well as portal films and allows extensive non-coplanar beams. It allows conformational therapy. This system probably takes more advantage of the potential of 3-D planning than any other system yet devised.
Thomas Griffin, M.D. then described the three-dimensional planning system evolved at the University of Washington. This presentation reviewed the three major aspects of 3-D planning systems including graphic displays, dose computation methods and ease of use. 3-D planning systems were first developed over 10 years ago but are only rarely used in clinical practice. Their conclusions are that adequate displays and computation techniques are now available but improved packaging, engineering and ease of use are required before 3-D planning will be widely practiced.
Michael Goitein, Ph.D. then discussed the evaluation and optimization of 3-D plans based on biological models of tumor control. He described an algorithm which has been developed to estimate tumor control probability in the face of inhomogeneous irradiation of the target volume. The program requires three pieces of data, the dose-volume histogram for the target volume, the likely tumor control probability if uniform radiation occurred and an estimate of the slope of the dose response curve. He concluded that tumor control might be better characterized by the mean rather than the minimum target absorbed dose, when dose non-uniformity is not too great. Modest dose deficits in small sub-volumes of the target may not be too deleterious and modest dose increments to substantial sub-volumes may be advantageous.
The optimization of 3-D plans based on biologic models of normal tissue and normal tissue complication was then discussed by John Lyman, Ph.D.. He concluded that dose volume histograms are a convenient tool to summarize a 3-D dose distribution and evaluate the plan in terms of normal tissue injury. A number of factors can be calculated and include the localization gain factor which compares the dose localization of two plans. This is calculated from the dose localization factor that measures how efficiently the energy is concentrated within a target volume. He concludes that with a suitable biologic model, dose volume histograms can be used to estimate a normal tissue complication probability. In combination with suitable tumor models, such as previously discussed by Dr. Goitein, the dose volume histogram can be used to estimate the probability of local control and the probability of local control without complication. This method appears quite useful and should be combined with future development of 3-D treatment planning systems.
Takehiro Nichidai, Ph.D. then presented a report on the CT simulator, a new 3-D planning simulation system for radiotherapy. A real time CT-linked treatment planning system called the CT simulator has been developed. It consist of a CT scanner, an multi-image display component and a treatment planning device that includes a laser beam projecting component to outline the designed portals on the patient. Thus, it can do both three-dimensional planning and simulation within a short time. The laser bean projecting device locates the beam center, the field sides, block localization and treatment position on the patient’s skin surface. Because of the ability to project the computer derived beams on the patient’s skin with the laser apparatus, subsequent localization films on a simulator are not necessary.
Hiroshi Tsujii, M.D. then reported further on the clinical application of the CT simulator. A unit similar to that described by Dr. Nishidai has also been installed at the Hokkaido University School of Medicine. They concluded that this new RT-CT system is valuable in terms of accurate performance of treatment planning and is in addition cost effective.
Robert Carlson, M.D. and Laurence Fagan, M.D. from Stanford then reported on artificial intelligences systems in oncology treatment planning. They reviewed the need for expert systems in oncology with particular emphasis on the need for assistance in management of complex patients, individualization of treatment and data management. They described one prototype system developed at Stanford known as Oncocin. This system aides in managing patients who are entered in specific treatment protocols. They felt that the knowledge learned from systems such as Oncocin could be transferred to radiotherapy treatment planning in particular in evaluating three-dimensional treatment plans and in integrating and optimizing multi-modality therapy. It is clear that expert systems will play a major role in the future and that they require extensive development.
The round table discussion then evaluated the status of three-dimensional treatment planning. It was agreed that it is the next major step in the development of conventional radiotherapy. The advantages include the implementation of conformational therapy through three-dimensional planning and the reduction in normal tissue injury as well as enhancement of tumor response through more accurate delivery of higher doses and through the use dose volume histograms. CT planning will also allow much more accurate beam direction as exemplified in the presentations on CT simulation systems with the laser beam port outline device. It is clear that new systems must be able to handle multi-images including CT and MRI, as well as port film data. The value of expert systems is just being studied. It is likely that they will be prove extremely valuable in autocontouring of tumors for example, in deriving optimal plans using various formulas based on dose volume histograms and in incorporating radiotherapy into multi-modality clinical trials.
A final session of the meeting then concentrated on a review of the present status of intraoperative radiation. This subject is of particular interest to the Japanese because it was evolved in the modern era in Japan.
Gerald Hanks, M.D. discussed the evolution and direction of intraoperative trials in the RTOG. He described a series of studies conducted by RTOG at the phase II level. These have concentrated on developing techniques and a cadre of interested and expert institutions to participate in future phase II studies. Evaluation has included carcinoma of pancreas, carcinoma of rectum, carcinoma of cervix and other sites. Future studies will evaluate IORT compared to conventional treatment only and in addition, will lock at chemical modifiers and protectors and other methods to improve the results of IORT.
Sunao Egawa, M.D. then presented a discussion of the physical aspects of the layout of an intraoperative radiotherapy unit. He also discussed his clinical experience with bladder cancer and pancreatic cancer at the National Cancer Center Hospital in Tokyo. He described the new microtron intraoperative facility with electrons between 3 and 22 MeV available. The facility was rebuilt in 1982 and includes an operating suite with a microtron. The microtron supplies two gantries, one used for standard X-ray irradiation and another in the operating room. In addition, the operating room can be isolated from the treatment room and both microtron rooms used for conventional patients. He then discussed the treatment of superficial bladder cancer with intraoperative irradiation. They have achieved a five year survival rate of 73% in the whole group including patients with T1 and T2 lesions. They felt that IORT is meritorious for bladder cancer for preservation of the bladder with a low frequency of recurrence. They also reported on encouraging initial result with radical surgery and intraoperative radiation, as well as chemotherapy for carcinoma of the pancreas.
Masao Matsutani, M.D. reported on IORT for glioblastoma multiforme. Treatment was given at doses of 15 to 20 Gy. It was accompanied by resection after previous external beam irradiation. In a group of 19 patients receiving IORT, 61% two year survival was observed.
Timothy Kinsella, M.D. then reported on the experience with intraoperative radiation at the National Cancer Institute in the United States. He reviewed the radiobiologic experiments in dogs which developed the tolerance for single dose intraoperative radiation for many organs. In general doses between 20 and 30 Gy are within the safe limit. Sites studies have included gastric and rectal cancer, pancreatic cancer, and retroperitoneal sarcomas.
Tomohiko Okawa, M.D. then discussed results of pre and intraoperative radiation in the treatment of rectal cancer at the Tokyo Women’s Medical College. Their experience indicates that adjuvant treatment with pre and intraoperative radiation for potentially operable rectal cancer leads to effective local control and is well tolerated.
The round table discussion reviewed the current status of IORT. It was felt that it is a useful modality, although difficult and expensive. Particularly encouraging results have been seen in rectal cancer as well as in smaller series for bladder cancer. The results with carcinoma of the pancreas are somewhat disappointing because of the dissemination of tumor to the peritoneal surface, liver and lungs. On the other hand, the best survival results reported have occurred with intraoperative radiotherapy for unresectable disease and the smaller randomized trials at the US NCI showed improved survival with intraoperative treatment post-resection. Further clinical trials and randomized studies are indicated.
This meeting was important to the continuation of cooperation between the U.S. and Japan in radiation oncology and combined modalities. The U.S. and Japan continue their deep interest in the development of hyperthermia with emphasis on better equipment for local as well as regional heating and on evolution of clinical trials. The U.S. and Japan have both developed a major interest in the construction and testing of new hyperthermia devices. The major problem at this time is the inability in many situations to heat evenly throughout the tumor. Thus, the involvement of manufactures in Japan and the U.S. in designing and producing new equipment, as well as the involvement of the universities in such design and construction will be essential. Close correlation between Japan and the U.S. could evolve better machines more rapidly as well as co-ordinate their clinical testing. The International Hyperthermia Meeting will be held in Kyoto, Japan this year and will offer further opportunity for interaction between the U.S. and Japan groups.
The development of sensitizers is going on with enthusiasm around the world. Major emphasis continues to occur in Japan and the U.S. Studies are concentrating on developing better agents, developing new agents such as those that kill hypoxic cells and in focused clinical trials. The results of this meeting indicate that there is significant potential for collaborative drug development with enhanced ability now in Japan. The group is particularly interested in developing trials of current best agents alone and in combination as well as in phase I testing of new agents.
Radiotherapy and chemotherapy continues to be a major interest of the U.S.-Japan group. It has shown significant benefit in a number of sites including head and neck, esophagus, rectum and anus, as well childhood malignancy. A major interest exists in a better understanding of the mechanism of interaction, the mechanism of cross resistance between radiation and cytotoxic drugs and the evolution of strategies to avoid such resistance.
Particle radiotherapy has achieved a large degree of cooperation and integration between the U.S. and Japan, the programs are now very complementary in that the evaluation of neutrons has been completed in Japan and is within a few of years of completion in the United States. Conclusions are similar in that a small group of sites have been found to benefit from neutron therapy with particular emphasis on salivary gland cancer. The program now is concentrating on the evaluation of charged particles with two proton units in Japan and one currently in use in the U.S. and one under construction in the U.S. The heavy particle facility at Lawrence Berkeley Laboratory will soon be joined by a new facility for acceleration of similar particles at the NIRS in Chiba, Japan. Thus, the opportunity will exist for large scale cooperative trials between the U.S. and Japan, both with protons and heavier particles, such as neon and silicon. The continuation of exchanges and integrated effort in this area is very important.
Three-dimensional treatment planning had its origins in the particle programs in the United States and Japan and has now come into its own as a major potential influence in conventional photon therapy. Its integration with CT based simulators and with treatment delivery system such as automatic block makers and automatic laser type patient surface delineation can lead to a major increase in the accuracy of radiotherapy. The use of dose volume histograms and predictors of tumor and normal tissue response will allow automated optimization of plans. Such automation and the maximal use of 3-D planning requires better and easier to use programs and in particular, artificial intelligence system to take much of the drudgery from the contouring of tumors in the comparison of multiple plans. Both the Japan and U.S groups appear well situated to exploit this new method. Closer cooperation in the future would be a major asset and could be achieved through the U.S.-Japan program.
Intraoperative radiation has been a major interest in Japan and more recently in the United States. It has been a subject for many of the U.S.-Japan cooperative meetings in the therapy area. It has been shown to be of a advantage in certain sites, such as post-operatively in stomach and pancreas and for marginally resectable rectal cancer. More recently studies in Japan have indicated a potential advantage in gliogblastoma and in bladder. Further interaction between the U.S. and Japanese group has been initiated.
This was an extremely exciting meeting and it emphasis the importance of continued collaboration in the major areas covered. The topics discussed encompassed the major areas of pre-clinical and clinical research in the two countries and all have shown significant progress. Particular advantage appears to exist in close collaboration in the development of hyperthermia equipment and in the development of new radiation sensitizers. Equipment and system development will also be furthered by close cooperation in the area of charged particles and the exciting new area of three-dimensional treatment planning.



SEMINAR AGENDA AND PARTICIPANTS

(1) SEMINAR ON THE ROLE OF CYTOKINES IN CANCER TREATMENT
November 4-5, 1987
Century Hyatt Hotel, Shinjuku, Tokyo,

AGENDA

November 4, 1987 (Wednesday)
8:55 a.m.	Welcome and Opening Remark	M. Ogawa
Session 1: Interferons
9:00-9:30	Interferon-!!!study in Japan	R. Ohno (Nagoya University)
9:30-10:00	Interferon-!!!study in US	K. Foon (Roswell Park Memorial Inst.)
10:00-10:30	Interfreon-!!!study in Japan	M. Ogawa (Cancer Chemotherapy Center)
10:30-11:00	Interferon-!!!study in US	S. Sachs (Genetech, Inc.)
11:00-12:00	Discussion
12:00-1:30	Lunch
Session 2: Interleukin-2 (IL-2)
1:30-2:00	IL2	T. Ogura (Tokushima University)
2:00-2:30	IL2 + LAK	T. Toge (Hiroshima University)
2:30-3:00	IL2 + LAK	C. Coltman (University of Texas)
3:00-3:30	IL2 + IFN	M. Saijo (National Cancer Center)
3:30-5:00	Discussion
5:00	Adjourn
November 5, 1987 (Thursday) Session 3: Combined Use of Cytokines & Chemotherapy
10:00-10:30	Interferon + Cytotoxic Drugs	T. Kataoka (Cancer Chemotherapy Center)
10:30-11:00	Interferon + Cytotoxic Drugs	E. Mihich (Roswell Park Memorial Inst.)
11:00-11:30	Interferon + Cytotoxics	M. Friedman (National Cancer Institute)
11:30-1:00	Lunch
Session 4: TNF
9:00-9:30	TNF Study in Japan	S. Niitsu (Sapporo University)
9:30-10:00	TNF Study in US	J. Kovach (Mayo Clinic)
Session 5: Future Perspectives
1:00-2:30	General Discussion
2:30	Closing Remark
3:00	Adjourn