Japanese Journal of Clinical Oncology

Fumihiro Katsura, Masao Eura, Kazuaki Chikamatsu, Masatake Oiso, Eiji Yumoto, Takeru Ishikawa

doi: 10.1093/jjco/hyd030pmid: 10798537

Background: The human MAGE-3 gene encodes tumor-specific antigens that are recognized by cytotoxic T lymphocytes (CTLs) and expressed in a high percentage of various malignant tumors. Of the five MAGE-3-derived CTL epitopes identified to date, two nonapeptides (TFPDLESEF and IMPKAGLLI, designated MAGE-3.A24a and MAGE-3.A24b, respectively) can be expressed on the tumor surface by binding to the HLA-A24 molecule, which is the most frequent HLA class I molecule in Asian populations. To compare the immunogenecities of the two peptides, individual specific CTL lines were generated for each peptide (MAGE-3.A24a and MAGE-3.A24b). Methods: Peripheral blood mononuclear cells (PBMCs) from four HLA-A24 + healthy donors were stimulated in vitro with autologous dendritic cells pulsed with MAGE-3.A24a, MAGE-3.A24b or both and were subsequently cultivated with a cytokine combination including interleukin-2. Results: We succeeded in generating peptide-specific CTL lines in two of the four donors. The two CTL lines showed similar cytolytic levels against three MAGE-3 + /HLA-A24 + cancer cell lines and also target cells pulsed with the corresponding peptide. Cytolytic activities were blocked by either anti-CD8 or anti-HLA-A24 monoclonal antibodies. Conclusions: The results suggest that MAGE-3.A24a and MAGE-3.A24b peptides have equal potential in inducing MAGE-3-specific and HLA-A24-restricted CTLs. Key words

Katsura, Fumihiro; Eura, Masao; Chikamatsu, Kazuaki; Oiso, Masatake; Yumoto, Eiji; Ishikawa, Takeru

doi: N/Apmid: N/A

Background: The human MAGE-3 gene encodes tumor-specific antigens that are recognized by cytotoxic T lymphocytes (CTLs) and expressed in a high percentage of various malignant tumors. Of the five MAGE-3-derived CTL epitopes identified to date, two nonapeptides (TFPDLESEF and IMPKAGLLI, designated MAGE-3.A24a and MAGE-3.A24b, respectively) can be expressed on the tumor surface by binding to the HLA-A24 molecule, which is the most frequent HLA class I molecule in Asian populations. To compare the immunogenecities of the two peptides, individual specific CTL lines were generated for each peptide (MAGE-3.A24a and MAGE-3.A24b).Methods: Peripheral blood mononuclear cells (PBMCs) from four HLA-A24+ healthy donors were stimulated in vitro with autologous dendritic cells pulsed with MAGE-3.A24a, MAGE-3.A24b or both and were subsequently cultivated with a cytokine combination including interleukin-2.Results: We succeeded in generating peptide-specific CTL lines in two of the four donors. The two CTL lines showed similar cytolytic levels against three MAGE-3+/HLA-A24+ cancer cell lines and also target cells pulsed with the corresponding peptide. Cytolytic activities were blocked by either anti-CD8 or anti-HLA-A24 monoclonal antibodies.Conclusions: The results suggest that MAGE-3.A24a and MAGE-3.A24b peptides have equal potential in inducing MAGE-3-specific and HLA-A24-restricted CTLs.

Mitsuhiro Fujishiro, Tetsu Shinkai, Minoru Fukuda, Tomohide Tamura, Yuichiro Ohe, Hideo Kunitoh, Hiroshi Nishiwaki, Ikuo Sekine, Yoshihiro Matsuno, Miyuki Niimi, Nagahiro Saijo

doi: 10.1093/jjco/hyd037pmid: N/A

Background: To determine the maximum-tolerated dose (MTD) and acceptable dose level of CPT-11 in combination with a 14-day continuous infusion of etoposide in patients with refractory advanced lung cancer (LC), especially small cell lung cancer (SCLC). Methods: Etoposide was administered continuously at 25 mg/m 2 /day for 14 days. The initial dose of CPT-11 was 40 mg/m 2 given as a 90-min intravenous infusion on days 1, 8 and 15 and the dose escalation of CPT-11 was planned in increments of 20 mg/m 2 until severe or life-threatening toxic effects were observed. Results: Eight refractory advanced LC patients entered this study, of whom two were not assessable for toxicity because of patient’s refusal and progressive disease. One treatment-related death due to pulmonary toxicity and one patient with hypotension who needed catechol­amine for more than 48 h were observed at a CPT-11 dose of 40 mg/m 2 . The MTD of CPT-11 was 40 mg/m 2 . Therapeutic efficacy could be assessed in six patients, of whom two achieved a partial response. Conclusions: This regimen was too toxic and the recommended dose was outside this study. One has to consider pulmonary toxicity when using CPT-11, especially for patients previously treated with cytotoxic agents for which pulmonary toxicity has been reported. Key words

Yee Chao, Ho-Chung Teng, Hung-Chang Hung, Kuang-Liang King, Chung-Pin Li, Kwan-Hwa Chi, Sang‐Hue Yen, Full-Young Chang

doi: 10.1093/jjco/hyd038pmid: 10798538

Background: Acute disseminated intravascular coagulation (DIC) is a rare but severe complication of gastric adenocarcinoma. Conventional treatments, such as fresh frozen plasma, platelet replacement and heparin injections, are disappointing. The only way to correct this fatal condition is to control the underlying cancer promptly by effective chemotherapy. Here the successful initial control of acute DIC in gastric cancer patients with weekly EEPFL chemotherapy is reported. Methods: Advanced gastric cancer patients complicated with acute DIC were eligible. Patients were treated with weekly EEPFL therapy (etoposide 40, epirubicin 10, cisplatin 25, 5-fluorouracil 2200 and leucovorin 120 mg/m 2 ). Response, survival and toxicity were evaluated. Results: From April 1997 to April 1999, six patients were included in this study. All patients received EEPFL chemotherapy. Clinical and laboratory evidence of acute DIC stabilized quickly after starting chemotherapy. Four patients showed a partial response, one stable disease and one progressive disease. The toxicity was mild and well tolerated. Median survival was 28 weeks (12, 14, 26, 30, 30 and 32 weeks). All patients suffered from a relapse of DIC after initial successful control and died within 30 days of clinical and laboratory evidence of acute DIC relapse. Conclusion: EEPFL therapy is an effective chemotherapy regimen for patients with advanced gastric cancer associated with acute DIC. The prognosis is poor if the DIC relapses after the initial successful control. Key words

Chao, Yee; Teng, Ho-Chung; Hung, Hung-Chang; King, Kuang-Liang; Li, Chung-Pin; Chi, Kwan-Hwa; Yen, Sang‐Hue; Chang, Full-Young

doi: N/Apmid: N/A

Background: Acute disseminated intravascular coagulation (DIC) is a rare but severe complication of gastric adenocarcinoma. Conventional treatments, such as fresh frozen plasma, platelet replacement and heparin injections, are disappointing. The only way to correct this fatal condition is to control the underlying cancer promptly by effective chemotherapy. Here the successful initial control of acute DIC in gastric cancer patients with weekly EEPFL chemotherapy is reported.Methods: Advanced gastric cancer patients complicated with acute DIC were eligible. Patients were treated with weekly EEPFL therapy (etoposide 40, epirubicin 10, cisplatin 25, 5-fluorouracil 2200 and leucovorin 120 mg/m2 ). Response, survival and toxicity were evaluated.Results: From April 1997 to April 1999, six patients were included in this study. All patients received EEPFL chemotherapy. Clinical and laboratory evidence of acute DIC stabilized quickly after starting chemotherapy. Four patients showed a partial response, one stable disease and one progressive disease. The toxicity was mild and well tolerated. Median survival was 28 weeks (12, 14, 26, 30, 30 and 32 weeks). All patients suffered from a relapse of DIC after initial successful control and died within 30 days of clinical and laboratory evidence of acute DIC relapse.Conclusion: EEPFL therapy is an effective chemotherapy regimen for patients with advanced gastric cancer associated with acute DIC. The prognosis is poor if the DIC relapses after the initial successful control.

Shin Egawa, Rikiya Takashima, Kazumasa Matsumoto, Hideyuki Mizoguchi, Sadahito Kuwao, Shiro Baba

doi: 10.1093/jjco/hyd029pmid: 10798539

Background: The zonal distribution and location of tumors in different subgroups of Japanese patients with clinically localized prostate cancer have not been fully described. The appropriate radiation treatment volume thus remains unclear. Methods: Radical prostatectomy specimens of 141 consecutive patients with clinically localized prostate cancer were examined by the whole organ step-section technique. The zonal distribution and location of tumors at different levels of the gland were investigated after stratification into patient subgroups based on preoperative clinicopathological findings and risk group assessment. Results: The median tumor volume was 2.8 cm 3 ; 72 patients (51.1%) had pathologically organ-confined disease (pT2). Higher risk groups showed a statistically significant increase in tumor volume and a decrease in the rate of pathologically confirmed organ confinement. Involvement of the anterior base was found infrequently in certain patient subgroups: in only one of 20 patients (5%) with preoperative PSA <4.0 ng/ml, in three of 19 patients (15.8%) with specimen Gleason scores of 2–4 and in two of 32 patients (6.3%) identified as low-risk. Conclusions: Infrequent involvement of the anterior base in low-risk patients may be an intrinsic feature of clinically localized prostate cancer. Treatment volume modifications in these patients that reduce the radiation dose to the anterior base may be justified to avoid acute and late genitourinary toxicities. Key words

Egawa, Shin; Takashima, Rikiya; Matsumoto, Kazumasa; Mizoguchi, Hideyuki; Kuwao, Sadahito; Baba, Shiro

doi: N/Apmid: N/A

Background: The zonal distribution and location of tumors in different subgroups of Japanese patients with clinically localized prostate cancer have not been fully described. The appropriate radiation treatment volume thus remains unclear.Methods: Radical prostatectomy specimens of 141 consecutive patients with clinically localized prostate cancer were examined by the whole organ step-section technique. The zonal distribution and location of tumors at different levels of the gland were investigated after stratification into patient subgroups based on preoperative clinicopathological findings and risk group assessment.Results: The median tumor volume was 2.8 cm3; 72 patients (51.1%) had pathologically organ-confined disease (pT2). Higher risk groups showed a statistically significant increase in tumor volume and a decrease in the rate of pathologically confirmed organ confinement. Involvement of the anterior base was found infrequently in certain patient subgroups: in only one of 20 patients (5%) with preoperative PSA <4.0 ng/ml, in three of 19 patients (15.8%) with specimen Gleason scores of 2–4 and in two of 32 patients (6.3%) identified as low-risk.Conclusions: Infrequent involvement of the anterior base in low-risk patients may be an intrinsic feature of clinically localized prostate cancer. Treatment volume modifications in these patients that reduce the radiation dose to the anterior base may be justified to avoid acute and late genitourinary toxicities.

Hideyuki Akaza, Yukio Homma, Kiyoki Okada, Masao Yokoyama, Nobuo Moriyama, Michiyuki Usami, Yoshihiko Hirao, Tomoyasu Tsushima, Yasuo Ohashi, Yoshio Aso, the Prostate Cancer Study Group

doi: 10.1093/jjco/hyd035pmid: 10798540

Background : The majority of patients with localized and some cases of locally advanced prostate cancer undergo radical prostatectomy. However, radical prostatectomy cannot always be selected for those patients. In this situation, primary hormone therapy is an alternative treatment option. We have designed a prospective randomized study of the effects of primary hormone therapy for such patients. Methods : A total of 151 patients with T1b, T1c, T2a, T2b or T3a prostate cancer who were not scheduled for radical prostatectomy were enrolled into this study. Patients were randomly allocated into two groups; Group I received luteinizing hormone-releasing hormone (LH-RH) agonist monotherapy (leuprorelin acetate depot, 3.75 mg monthly) and Group II received LH-RH agonist in combination with chlormadinone acetate (100 mg/day). Effects on serum prostate-specific antigen level, progression-free survival and survival were observed for 2 years. Results : The reasons why radical prostatectomy was not scheduled were poor risk for surgery (38%), patient’s wish (32%) and physician’s recommendation (30%). After 12 weeks of treatment, 49% of the patients in both groups showed a complete response (CR). Of the patients showing a partial response (PR) after 12 weeks of treatment, 25% in Group I and 52% in Group II improved to CR 1 year later ( p < 0.05). Group II showed a longer progression-free survival ( p < 0.05). Progression-free survival rates were 62% (Group I) and 91% (Group II) in T2b patients and 43% (Group I) and 73% (Group II) in T3 patients. Only one patient in each group died from prostate cancer. Conclusions : Early primary hormone therapy is a reasonable treatment option for localized or locally advanced prostate cancer patients if radical prostatectomy was not scheduled. Chlormadinone acetate showed an additive effect with LH-RH agonist, at least in 2 years’ observation. Key words

Akaza, Hideyuki; Homma, Yukio; Okada, Kiyoki; Yokoyama, Masao; Moriyama, Nobuo; Usami, Michiyuki; Hirao, Yoshihiko; Tsushima, Tomoyasu; Ohashi, Yasuo; Aso, Yoshio; Prostate Cancer Study Group, the

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Yasuo Horikoshi, Jun-ichi Mimaya, Koji Amano, Yoshifumi Kawano, Arata Watanabe, Tsutomu Watanabe, Isao Sekine, Kenichi Nishikawa, Yuriko Tsunematsu, Mikiya Endo, Haruhiko Eguchi, Teruhisa Koyama, Kiyoshi Kawakami, Toshiaki Oka, Takeji Matsushita, Shoichi Koizumi, Takeo Fujimoto, Yoichi Takaue

doi: 10.1093/jjco/hyd033pmid: 10798541

Background: The primary object of this study was to identify treatment-related variables that may predict relapse of acute myelogenous leukemia (AML) after autologous peripheral blood stem cell transplantation (PBSCT), which will be critical for the development of a suitable proto­col for wider application. Methods: A total of 28 children (age 0–18 years) with AML underwent PBSCT and have had a minimum follow-up of 25 months; including 24 patients in their first complete remission (CR) and four in their second CR. The patients were divided into two cohorts according to the study phase: 16 patients were treated in an early phase pilot study and 12 patients in their first CR were treated in a prospective trial. Fifteen of the first-CR patients had any of the cited high-risk features of high WBC count (>100 × 10 9 /l; n = 5), FAB M0/M4/M5/M7 subtypes ( n = 11) or delayed achievement of CR ( n = 9). Except in one patient, cytoreductive regimens did not include total body irradiation (TBI). Results: After PBSCT, one patient died of veno-occulsive disease (VOD) and another patient relapsed early on day 43, but the remaining patients showed engraftment. Leukemic relapse was observed 1–29 months after PBSCT (median, 8 months ); in all of the 4 children treated in their second CR and in 11 of the 24 patients (46%) treated in their first CR. The remaining patients have been disease-free for 24 to 97 months (median, 53 months ). Using a multivariate analysis, the timing of apheresis was the most significant prognostic factor for those treated in their first CR ( p = 0.03); 12 of the 16 patients whose PBSC were collected beyond 2.5 months of CR continue to remain in CR, while seven of the eight patients whose PBSC were harvested within 2.5 months of CR relapsed. Conclusion: Although the small number of patients studied does not allow firm conclusions to be drawn regarding the relative effectiveness of this therapy, the results do suggest the feasibility of further studies of PBSCT for the treatment of childhood AML with high-risk features including the assessment of minimum residual disease. Key words