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Krukenberg's tumor, an metastatic ovarian tumor originating from gastric cancer, is a disease with extremely poor prognosis, and it is rare for patients to survive for more than 2 years after the diagnosis. We encountered a patient in whom a long-term good prognosis could be obtained probably because of the effects of chemotherapy after the ovarian tumor extraction. This patient was treated by a combination of UFT and cisplatin. Enhancement of the antitumor effects by the concomitant use of 5-FU and cisplatin has been attracting attention, and the methods of administration of these drugs have been investigated by numerous researchers as FP therapy. It was characteristic to the treatment of our patient that 5-FU was administered in the form of oral UFT. We believe this was an important experience suggesting that this administration method is safe and effective, and even influences the long-term prognosis.

Objectives: To evaluate drug-induced neurotoxicity with combination consecutive low-dose CDDP (CLD-CDDP) and weekly paclitaxel in comparison with TJ therapy. Neurotoxicity was judged according to accumulative scores on questionnaires., Subjects and Methods: Weekly TP therapy (CDDP: 10 mg/m2, days 1-7, paclitaxel: 60-80 mg/m2, days 1, 8, 15) and TJ therapy (paclitaxel: 170-180 mg/m2, 3 hours, carboplatin AUC 4-5) were given to 24 subjects in 57 courses and 19 subjects in 30 courses as previously reported, respectively., Results: 1. Significant differences were found in numbness accumulative scores (p = 0.011) between weekly TP and TJ therapy, but not in pain accumulative scores (p = 0.926) between weekly TP and TJ therapy. 2. Peak pain at days 3-4 of paclitaxel that appeared during TJ therapy disappeared during weekly TP therapy, while numbness persisted to a lesser extent with weekly TP therapy than with TJ therapy. 3. Numbness was observed to accumulate in some subjects but not in others during weekly TP therapy., Conclusion: The patients' subjective symptoms were able to be objectively evaluated with the questionnaires. Weekly paclitaxel was observed to reduce neurotoxicity, which might be reinforced in combination with CDDP.

Combination therapy using HCFU and TNP 470, which inhibits angiogenesis, was examined for effectiveness against the footpad injection model of LMFS tumor. This LMFS, a retroperitoneal sarcoma of BALB/c mice, proliferated at the inoculation site (100% take) and all mice operated on after day 15 had spontaneous metastatic nodules in the liver. Mice with the LMFS tumor were given HCFU and 5-FU (5 days/week), and/or TNP 470 (3 days/week) from day 3 for 3 weeks and sacrified at day 28 under anesthesia. Seven of 10 mice receiving 5-FU and TNP 470 died from the side effects of the drugs. Mean tumor weight and liver metastatic nodules were determined and compared with a control group. The results were as follows: HCFU group: 94.6%, 11.8%, 5 FU group: 73.9%, 28.8%, TNP 470 group: 67.6%, 44%, HCFU and TNP 470 group: 33.3%, 6.4%. Mice with LMFS were given HCFU and/or TNP 470 from day 3 for 4 weeks. The foot on the injected side was amputated on day 15, and the animals were sacrified on day 35. Liver metastatic nodules compared with those of the operation (OP) group as follows: OP + HCFU group: 14.4%, OP + TNP group: 39.1%, and OP + HCFU + TNP 470 group: 5.4%. Histologically, 5 of 5 mice of the OP group, 3 of 5 of the OP + HCFU group, 4 of 5 of the OP + TNP 470 group and 1 of 5 of the OP + HCFU + TNP 470 group had liver metastases. These results show that while either HCFU or TNP 470 is effective by itself, a combination of these drugs is more effective against liver metastasis.

CDDP is generally given in a bolus fashion because it has been considered to act in a dose-dependent manner. However, early studies demonstrated anti-tumor activity of CDDP was both dose- and time-dependent. This indicated that the anti-tumor effect of CDDP dependent on the area under the concentration of filterable platinum-time curve (AUC) obtained following an administration of the agent, but not on the maximum concentration (C max) of the agent. To increase the AUC and treatment compliance, we designed a consecutive low-dose CDDP dosing method (10 mg/m2, days 1-7). This method was found to be accompanied by a good treatment compliance and high dose intensity due to significantly reduced toxic effects when CDDP was combined with several other agents. 5-FU alone has been reported to be effective in approximately 20-25% of gynecologic malignancies. Moreover, CDDP can augment the cytotoxic activity of 5-FU through biochemical modulation. Accordingly, combination treatment with consecutive low-dose CDDP with 5-FU could be designed. The present report reviews the efficacy of this combination chemotherapy for cervical carcinoma.

Gynecological tumors of cervix uteri, corpus uteri, ovary, vagina, and vulva are classified by the TNM systems. The definitions of the T categories correspond to several stages accepted by FIGO (Federation Internationale de Gynecologie et d'Obstetrique). Those of regional lymph nodes are different among primary sites. The relationships between 5-year survival rates and TNM stages were investigated in cervical and endometrial carcinoma cases in 1985 by the Japan Society of Obstetrics and Gynecology (JSOG). The pTNM pathological classification had a better relationship with survival than the TNM clinical classification, respectively. According to the rules for TNM classification, T categories should be assessed by physical examination, cytoscopy and urography. These data indicate that prognostic factors could not be accurately assessed by these procedures. Radiotherapy for cervical carcinoma is selected in many cases. The JSOG adopts the clinical classification in 1997, but it had a pathological classification for corpus uteri and ovary in 1995.

A new spontaneous liver metastasis model from LMFS tumor, a retroperitoneal sarcoma of BALB/c mouse origin, was reported. After a subcutaneous injection of LMFS cells in the footpad, amputation of the leg was performed every 5 days from day 5 to day 20, and mice were killed at day 25 under anesthesia. The LMFS cells proliferated at the inoculation site (100% take), and all mice operated after day 15 had metastatic nodules spontaneously in the liver. Local recurrence was not observed in any cases. Liver weight was correlated with tumor growth in the liver. The combination therapy of operation and HCFU was examined in comparison with the footpad injection model. The foot on the injection side was amputated on day 12 with or without HCFU administration, and mice were sacrificed on day 33 under anesthesia. Histological liver metastases were as follows: 1. no treatments: 100%; 2. early phase chemotherapy without operation: 80%; 3. operation without chemotherapy: 80%; 4. postoperative chemotherapy: 20%; 5. preoperative chemotherapy: 40%; and 6. late phase chemotherapy without operation: 100%. These results indicate that operation with chemotherapy is the most useful treatment for liver metastases. Using this liver metastatic model, we are investigating a new combination therapy of operation and anti-cancer drugs for liver metastases.

Among advanced ovarian cancer, OCCA has worse prognosis compared with serous cystadenocarcinoma because of its poor sensitivity to CDDP-based chemotherapy (CTX). Indeed, there has ever been no one patient with pure OCCA showing an appreciable response to CTX. OCCA has recently been increasing in prevalence and has occupied approximately 20-25% of all ovarian cancer. Thus, there is an urgent need to find effective regimens. Based on the results of chemosensitivity tests previously performed both in vitro and in vivo, we designed a combination of CPT (140 mg/m2, i.v.-infused over 4 hours on day 1, 15, and 29) and MMC (7 mg/m2, i.p. injection through a reservoir on day 1, 15, and 29). The course was repeated every 4 weeks. To date 10 pts were entered The median age was 53 (41-69). Among total 25 courses, grade 3 diarrhea was observed in 3 courses. Other toxic signs were acceptable. The responses by tumor size were 2 CR for disease < or = 2 cm in diameter, and 2 CR, 2 PR, 2 NC, and 2 PD for > 2 cm. Six responders showed a significantly longer survival compared with 4 non-responders (p < 0.0396 for Log-rank test). Thus, the present protocol is the first to demonstrate a significant activity for pure OCCA.

Seven patients with recurrent gynecological malignancies (2 cervical, 2 endometrial, 3 ovarian) treated with CDDP at the initial chemotherapy were studied for the pharmacokinetic analysis of platinum (Pt) and changes of blood biochemistry in the continuous CDDP-CBDCA infusion therapy. All the patients were indwelled of the total parenteral nutrition catheter. A balloon type infuser (Baxter Inc., multiday type) was connected with the catheter and the drugs were infused continuously through it. CBDCA was infused continuously from day 1 through day 5 at a daily dose of 60 mg/m2, followed by continuous CDDP infusion from day 6 through day 30 at a daily dose of 2.5 mg/m2. All the patients received 3 courses of the treatment. The area under the [Pt]-time curve (AUC) of filterable Pt was as high as 60.98 +/- 8.20 mg.hr/ml (mean +/- SE), and that of total Pt 691.48 +/- 93.61 mg.hr/ml. However, the Cmax of filterable Pt was as low as around 400 ng/ml during day 1 to 6, and around 20 ng/ml during day 7 to day 30. As to the toxicity, only slight myelosuppression but no renal and gastrointestinal toxicity were observed in this therapy. The quality of life of the patients received this treatment were maintained well throughout of the therapy. Responders were evaluated as 1 CR, 2 PR, 2 NC and 1 PD. These data indicated that high AUC but low Cmax of filterable Pt by continuous CDDP-CBDCA therapy resulted in less toxicity. Further investigation was warranted to evaluate the efficacy of continuous CDDP-CBDCA therapy.

A permanent cell line, termed LMFS (liver metastasis from sarcoma) was established in vivo and in vitro from a spontaneously occurring murine retroperitoneal tumor of BALB/c mouse origin. After a subcutaneous injection of more than 1 x 10(5) cells in the dorsal side of mice, the LMFS cells proliferated at the inoculation site (100% take) and induced metastatic nodules spontaneously in the liver but not in the lung. The antitumor effects of 5'-DFUR against the LM FS tumor were examined. Mice with the LMFS tumor were given 5'-DFUR (0, 0.75, 1.5, 3.0 mM/kg) per os for 7 days from day 21 through day 27. Prolonging of the survival period was observed by the 5'-DFUR administration and the increase in the liver weight, which reflects tumor growth in the liver, was suppressed. Mice with the LMFS tumor were given 5'-DFUR (0, 0.75, 3.0 mM/kg) every day without Saturday and Sunday from day 21. Mean survival time of the control group was 57.8 +/- 4.9 days. And that of 5'-DFUR groups (0.75, 3.0 mM/kg) was 72.1 +/- 16.0 day (p < 0.05), and 80.5 +/- 9.5 days (p < 0.001), respectively. These results reveal that 5'-DFUR is effective for not only the primary site but also the liver metastasis.

Twenty-two patients with ovarian cancer stage III and IV received combination chemotherapy with CDDP, adriamycin (ADM) and cyclophosphamide (CPM), and were studied for response and side-effects. Patients were divided into two groups according to the following CDDP infusion schedules. (CAP 1) CDDP 7mg/sqm/8 hrs/saline 500 ml/d1-d10, ADM 35 mg/sqm/d1, CPM 350 mg/sqm/d1: 8 cases; (CAP 2) CDDP 70 mg/sqm/2 hrs/d1, ADM 35 mg/sqm/d1, CPM 350 mg/sqm/d1: 14 cases. The overall response rate (CR + PR) was 62.5% in CAP 1, and 50% in CAP 2 (on statistical difference: NS). The 3-year survival rate was 54.7% in CAP 1 and 38.5% in CAP 2 (NS). Side effects of nausea, vomiting and nephrotoxicities were remarkably reduced in CAP 1. These data suggest that lower concentration and longer infusion time of CDDP administration increases the therapeutic index. This infusion schedule is suitable for chemotherapy at home or on an outpatient clinic basis, especially in patients with ovarian cancer.

One of the most characteristic features of epithelial ovarian cancer is its inherent heterogeneity with respect to biological behavior ranging from the relatively indolent nature of borderline tumors to highly aggressive malignant diseases. This can be reflected in a wide variety of prognostic factors, among which the stage of disease is by far the most important, followed by histologic subtype, histologic grade, volume of residual disease, age at diagnosis, and performance status (PS). Within a given stage, histologic grade is the most powerful prognostic factor in stage I disease, followed by dense adherence and large volume of ascites. On the other hand, the main prognostic factor in more advanced stage disease (II-IV) includes an effect of chemotherapy and a volume of residuum, and PS. However, these factors alone cannot always predict patients' survival correctly. A number of new and potentially valuable prognostic factors have emerged as a result of the recent technical advances in molecular genetics, flow cytometric analysis, development of monoclonal antibody, immunohistochemical study, and steroid hormone receptor analysis. This article reviews some of these newly developed "investigational" prognostic variables, as well as the "widely accepted" clinicopathological prognostic factors.

Sixteen patients with recurrent gynecologic cancer were studied to evaluate maintenance of housewife activity and the quality of familiar interactions by the home continuous infusion of CDDP at a daily dose of 5 mg/body. A total dose of CDDP in one course was 100 mg/body, and more than one course was performed in every patient. Eight patients underwent intra-arterial infusion of CDDP by the 20-day continuous infusion and another 8 patients intra-venous infusion by 5-day continuous infusion every other week. The average caloric intake was 2201 kcal measured by the record of a three-day food intake during the treatment. 88% of the patients arouse between 6 and 7 in the morning, and all the patients cooked breakfast and supper, went shopping for food materials, cleaned a house and did the washing with the help of her family. All the patients accepted the treatment and were satisfied with it but appeared anxious about recurrence. Information or advice by the doctor was important to relieve their anxiety. Their husbands also accepted the treatment and tolerated well their wives, continuation of home therapy.

A late phase II study of CPT-11, a new derivative of camptothecin, in uterine cervical cancer and ovarian cancer was carried out by a cooperative study group at 26 institutions. Out of 144 patients enrolled, total cases were 110, involving 55 uterine cervical cancers and 55 ovarian cancers. In uterine cervical cancer, 5 cases of complete response (CR) and 8 cases of partial response (PR) were observed, with a response rate of 23.6% and a CR rate of 9.1%. In ovarian cancer, 13 cases of PR were observed, response rate was 23.6%. Both in uterine cervical cancer and ovarian cancer, the 95% confidence interval of response rate was 12.4-34.8%. In cases having undergone previous chemotherapy including platinum, derivatives, the response rate in ovarian cancer was 23.1% (12/52). In cases of uterine cervical cancer having previous radiotherapy, the response rate was 26.8% (11/41). In ovarian cancer of various histological types, a response was observed for not only serous cystadenocarcinoma but also mucinous cystadenocarcinoma, etc. A response was observed in distant metastatic lesions such as lung metastasis as well as primary lesion in uterine cervical cancer and ovarian cancer. Major adverse reactions were leukopenia, nausea and vomiting, diarrhea and anorexia, and these incidences (grade 2 or more) were 87.3, 60.3, 44.0 and 67.2%, respectively. Since some patients experienced severe adverse reactions, caution should be taken in treatment with CPT-11. Besides these reactions, alopecia was observed (33.1%), but severe adverse reactions such as nephropathy were not found. No significant difference in the efficacy and adverse reactions were observed between administration methods; A, 100 mg/m2 once weekly and B, 150 mg/m2 once every 2 weeks. Both were thought to be clinically useful. These results suggest that CPT-11 is clinically effective against uterine cervical cancer and ovarian cancer.

TNF, IL-1, IFN-gamma and PGE2 secretion of peritoneal macrophage obtained by peritoneal washing at the first day after laparotomy from 19 patients with cervical cancer and 19 with ovarian cancer, who were treated with sizofiran (SPG) intramuscularly before laparotomy or with recombinant interferon gamma (rIFN) intraperitoneally at the day of laparotomy, were studied. Treatment with SPG and rIFN significantly increased the number and secretion of TNF, IL-1 and IFN-gamma (p less than 0.05) but not that of PGE2. A high correlation between secretion of TNF and IFN-gamma (r = 0.99, p less than 0.01) was observed. These data suggest that potent tumoricidal activity of peritoneal macrophage obtained from the patients with gynecological malignancies could be expected by the treatment with SPG and rIFN due to the increased secretion of TNF, IFN-gamma and IL-1 and inhibition of increased secretion of PGE2.

Twenty nine patients with ovarian cancer of common epitherial origin who had no evidence of disease proved by computed tomography after the initial operation and chemotherapy were studied. The patients were randomized into two groups; (A) administration of UFT (1-(2-tetrahydrofuryl)-5-fluorouracil mixed with uracil) orally at a daily dose of 300 mg, 12 cases, (B) no further therapy, 17 cases. The therapeutic efficacy of UFT was assessed pathologically at the second look laparotomy (SLL). Plasma levels of 5-FU, tegafur and uracil were determined once a month to check whether patients intake UFT regularly or not. There were no significant difference in the mean age, in the distribution of numbers of patients in FIGO stage and histological cell type, in the mean total doses of CDDP and doxorubicin given at the initial chemotherapy [CDDP: (A) 352 +/- 152 mg, (B) 464 +/- 192 mg, doxorubicin: (A) 118 +/- 76 mg, (B) 119 +/- 92 mg] and in the duration between the initial operation and the SLL [(A) 484 +/- 154 days, (B) 414 +/- 274 days] between the two groups. The mean periods in the administration of UFT were 484.3 +/- 154 days. Recurrence was identified at the SLL in 1 case (8.3%) at paraaortic lymph nodes in (A) and 3 cases (17.6%) at the mesenterium, cul-de-sac and ascitic fluids in (B). No significant difference of recurrence ratio was observed between the two. Further long-term observation is required to assess the advantage of administration of UFT.

Between 1949 and 1987, 84 cases of primary vulvar malignancy were treated at the Cancer Institute Hospital. These cases accounted for 0.8% of the total number of gynecologic malignancies at our hospital during the same period. The clinicopathological findings were described. The mean age of the 84 cases was 61.7 years. The most frequent symptom was a vulvar mass, seen in 35 cases (41.7%). In preoperative cytologic examination of vulvar smears, 44/78 cases (56.4%) had suspected malignancy. Histopathologically, 57 cases (67.9%) were found to be squamous cell carcinoma. According to FIG0 staging system, there were 4 (4.8%) stage 0 tumors, 11 (13.0%) stage I tumors, 25 (29.8%) stage II tumors, 41 (48.8%) stage III tumors, and 3 (3.6%) stage IV tumors. The patients were treated by operation and/or irradiation. The five-year survival rate was 51.4% (36/70) in all stages. The five-year survival rate was 66.7% (2/3) in stage 0 cases, 87.5% (7/8) in stage I, 78.9% (15/19) in stage II, 28.9% (11/38) in stage III, and 50.0% (1/2) in stage IV, respectively. In patients treated by radical vulvectomy, the five-year survival rate was 26.7% (4/15) when there was inguinal nodal metastasis, and 73.7% (14/19) when there was no inguinal nodal metastasis. The five-year survival rate was 59.5% (25/42) in cases treated by operation and was 39.3% (11/28) in cases treated by irradiation. In preoperative adjuvant chemotherapy, the histopathological effect was 44.4% (4/9). In conclusion, the first choice for treatment of vulvar malignancy was considered the operative method.

The combined effect of cisplatin (CDDP) and aclarubicin (ACR) which was reported to inhibit the repair of the sublethal and the potentially lethal X-ray damages, was studied with human lymphocytes. The cell kinetics during administration of CDDP or ACR were analysed by flow cytometry. CDDP at the concentration of 0.5 microgram/ml had no effect on the cell progression. ACR blocked the cell progression at G1 period at the concentrations of 100 and 200 ng/ml, but the number of dead cells was not increased. When these two agents were combined, the number of dead cells increased more than 10 times compared to that of ACR alone. In conclusion, it was found that the combination of CDDP with ACR had a synergistic effect.