Cisplatin and ovarian carcinoma--early detection of cisplatin-induced nephrotoxicity

Cis-dichlorodiammine platinum (CDDP) has recently been introduced for the treatment of human malignancies. CDDP belongs to the group of heavy metals and has nephrotoxicity, whose side effects limit the dose that can be used in patients. The urinary excretion of lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (gamma-GTP), alkaline phosphatase (ALP), arylamidase (AA) activity and beta 2-microglobulin was determined in ovarian cancer patients receiving sequential combination chemotherapy with CDDP, adriamycin (ADM) and cyclophosphamide (CPA) (PAC chemotherapy) to evaluate the sensitivity of these indices for acute renal tubular damage and compared with the change in serum BUN, Cr and Ccr values. Increases in enzyme excretion after PAC chemotherapy were more often noticed and the urinary enzyme activity varied up to the 10.4-fold of the control, while serum BUN, Cr and Ccr values remained almost within normal limits. Enzyme excretion returned almost to the normal value in one week. A comparison between the urinary enzyme excretion especially AA value and serum BUN, Cr and Ccr values indicated that the serial determination of the urinary AA excretion pattern is more useful in detecting CDDP-induced nephrotoxicity than that of serum BUN, Cr and Ccr values.     

The study of cyclic maintenance chemotherapy with cisplatin, adriamycin, and cyclophosphamide (cyclic PAC chemotherapy) in patients with advanced ovarian cancer

The efficacy of two methods of chemotherapy in the treatment of patients with advanced ovarian cancer was compared on the basis of survival curves; one consisted of remission induction therapy alone with a combination of cisplatin (CDDP), adriamycin (ADM) and cyclophosphamide (CPM) (induction PAC therapy), and the other consisted of induction PAC therapy and additional maintenance therapy with cyclic PAC (cyclic PAC therapy). The subjects of the study were patients with advanced ovarian cancer in stages III and IV. Sixty-eight patients received induction PAC therapy alone and seventeen patients received both induction and cyclic PAC therapy. Demographic factors such as age at initial presentation, the stage of cancer (III or IV), surgical procedure, histological classification, number of courses of induction PAC, response rate, site of residual tumor after surgery and induction PAC therapy, and reduction rate of CA125 were compared in the two groups. When analyzed by the chi 2 test, none of these factors was significantly different in the two groups. Patients in the induction PAC therapy group received a median total dosage of CDDP 360 mg, ADM 235mg, and CPM 2.246mg. Patients in the cyclic PAC therapy group received CDDP 592mg, ADM 490mg, and CPM 4.642mg. Thus, the dosage of anticancer agents administered to the latter group was about twice as great as that administered to the former group. According to the Kaplan-Meier method, survival rates for the induction PAC therapy group were 88.2% for one year, 50.0% for two years, 28.0% for three years, and 8.8% for five years. The median survival period was 23 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preventive effect of urinastatin on cisplatin induced nephrotoxicity in rabbits

The effect of urinastatin (US) on the prevention of cis-diamminedichloroplatinum (CDDP) induced nephrotoxicity was examined in experiments on rabbits. They were divided into seven groups and treated intravenously as follows: Group 1; intravenous injection of CDDP 3mg/kg only, Group 2; 3% sodium chloride (15ml/kg/h, 1h) + CDDP, Group 3; 3% sodium chloride + CDDP + US (10,000U/kg), Group 4; Hydration A (350ml/body) + 3% sodium chloride + CDDP, Group 5; Hydration A + 3% sodium chloride + CDDP + US, Group 6; Hydration B (200ml/body) + 3% sodium chloride + CDDP, Group 7; Hydration B + 3% sodium chloride + CDDP + US. Creatinine clearance (Ccr) value, arylamidase (AA) activity in urine and gamma-glutamyltranspeptidase (gamma-GTP) activity in urine were consecutively measured as indices of nephrotoxicity. Ccr values in groups 1-3 significantly decreased markedly whereas those in groups 4-7 did not. The change in AA activity and gamma-GTP activity in urine suggests that no nephrotoxicity occurred in groups 5 and 7. Consequently, this experiment indicated that nephrotoxicity was prevented when CDDP was administered in 200mg/body hydration with both 3% sodium chloride and US. The recommended dose of US seems to be a 2,000U/kg intravenous injection before CDDP administration, followed by 8,000U/kg intravenous drip infusion for 2 hours after CDDP administration.     

Prevention of cisplatin induced nephrotoxicity by administering urinastatin to rabbits--comparison with other protease inhibitors

The present study was performed to evaluate the mechanism of the protective effect of urinastatin (US) against cisplatin (CDDP) induced nephrotoxicity. We measured consecutively the change in the creatinine clearance (Ccr) level, urinary arylamidase (AA) activity, and urinary gamma-glutamyl transpeptidase (gamma-GTP) activity as the indices of nephrotoxicity. These drugs such as US (10,000 U/kg, 3h: group 1), gabexate mesilate (2mg/kg/h, 4h: group 2), and aprotinin (5,000 U/kg/h, 4h: group 3) as protease inhibitors, and dopamine HCl (0.3mg/kg/h, 4h: group 4) for the increase in renal blood flow were used with the hydration of 15 ml/kg/h during 4 hours of experiments on rabbits. The change in the Ccr value after the intravenous administration of CDDP indicated that the level in groups 3, 4 decreased significantly at one day after the administration of CDDP. On the other hand, there was little significant increase in urinary AA activity and/or urinary gamma-GTP activity in group 1, while a transitional increase was observed in groups 2, 3, and 4, among which the highest level was found in group 4. These results are attributed to the protective action of US against CDDP mainly in the inhibition of the lysosomal enzyme released by the destruction of lysosomes in the proximal tubule cells of the kidney.     

The effect of metoclopramide, dexamethasone and antihistamine in the prevention of PAC chemotherapy-induced emesis

The effect of antiemetic agents on the nausea and emesis of ovarian cancer patients treated with CDDP (45 mg/m2), ADM (45 mg/m2) and CPM (450 mg/m2) combination chemotherapy was examined in a randomized parallel study. Metoclopramide (1 mg/kg, 4 times every 2.5 hours), dexamethasone (3.8 mg, 4 times every 2.5 hours) and antihistamine (10 mg, 2 times every 5 hours) were used as antiemetic agents and these agents were gradually decreased for 5 days. The above regimen significantly suppressed the frequency and volume of vomiting on the day of the first PAC chemotherapy but showed no effect on the delayed persistent nausea during chemotherapy. The frequency and volume of vomiting on the day of chemotherapy were 1.6 times and 102 ml respectively in the antiemetic group, but 8.9 times and 352 ml, respectively, in the control group. Although this antiemetic regimen sufficiently suppressed acute drug-induced emesis during chemotherapy, delayed persistent nausea was not eliminated. We next investigated whether these combined antiemetic agents protected the quality of life of patients during maintenance chemotherapy. Our data indicated that about 2 weeks was necessary to recover health after maintenance PAC chemotherapy. These results indicated that this regimen was effective in suppressing the acute drug-induced emesis and in maintaining the quality of life following maintenance PAC chemotherapy.     

The effect of bismuth subnitrate on cisplatin toxicity

Bismuth subnitrate (BSN), a bismuth compound medically used for antidiarrheics, was orally administered to see whether it can reduce CDDP nephrotoxicity or not. Thirteen patients aged 19 approximately 60 with ovarian cancer entered this BSN-CDDP trial. A total of thirty three courses of BSN-CDDP treatment was undergone. BSN was administered orally at a dose of 50 mg/kg for five days before CDDP therapy. CDDP was infused for two hours. No vigorous hydration or diuresis was performed. Only 2,000 ml of saline with 20 mEq per liter of KCl was given for post-hydration. The median dose of CDDP was 100 mg/m2. The renal toxicity of BSN-CDDP treatment was minimum. 82% of the courses at the sixth day after the treatment had creatinine clearance levels which were more than 80% of those before the treatment. But twenty-four hour NAG and beta 2-microglobulin excretion were significantly increased. Bone marrow suppression and gastrointestinal disturbance were commonly observed. The results of our study indicate that BSN pretreatment reduces the renal toxicity of CDDP to some extent.     

端粒酶激活与上皮性卵巢癌化疗敏感性及其预后的关系

目的：探讨端粒酶活性水平对卵巢化疗疗效及预后影响。方法：以TRAP－PCR－ELISA法检测卵巢癌组织中端粒酶活性;以MTT法检测卵巢癌细胞对CDDP、ADM敏感。结果：22例卵巢癌组织中,端粒酶阴性者3例（13．64％）,阳性者19例（86．36％）。8例端粒酶活性高于2U者,PAC方案化疗有效者5例（62．5％）,11例端粒酶活性低于2U者,化疗均有效（100％）。端粒酶活性高于2U者,进展与复发或死亡5例（62．5％）,而端粒酶活性低于2U者仅1例出现复发,无死亡。结论：随着端粒酶活性增高,卵巢癌对CDDP、ADM敏感性下降。     

原发性肾病综合征患儿血脂代谢紊乱的肾毒性作用

目的探讨原发性肾病综合征患儿(PNS)血脂代谢紊乱与肾功能改变的关系。 方法2004 01—2006 01，根据肾功能检查结果，将广西医科大学第一附属医院儿科收治的76例PNS患儿分成无肾功能损害组(46例)与肾功能损害组(30例)，检测血浆总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、非 高密度脂蛋白(non HDL)、低密度脂蛋白(LDL)、载脂蛋白A1(ApoA1)、载脂蛋白B(ApoB)、ApoA1/B、血浆尿素氮(BUN)、肌酐清除率(Ccr)和尿酸(UA)等指标。 结果(1)肾功能损害组TG、BUN、Ccr和UA均明显高于无肾功能损害组；(2)76例PNS患儿TG与Ccr及UA呈高度正相关(P<0.01)，ApoA1与Ccr呈中度正相关(P<0.05)，ApoB与UA呈中度正相关(P<0.05)；(3)76例PNS患儿non HDL与LDL呈高度正相关(P<0.01)。 结论PNS合并肾功能损害的血脂代谢紊乱以TG显著增高为特征；TG和non HDL变化可以作为临床判断PNS患儿肾功能损害程度及调脂措施有效性的指标。     

Chemotherapy of ovarian cancer based on in vitro (HTCA) and in vivo (nude mice) chemosensitivity testing

The human tumor clonogenic assay (HTCA) and the human tumor xenograft system implanted in nude mice were performed simultaneously in an ovarian cancer patient as chemosensitivity testing. Eight anticancer drugs (5-FU, MMC, VCR, ACD, BLM, VLB, CDDP, and ADM) were applied to the HTCA and the human tumor xenograft system. In the HTCA, 5-FU and MMC were sensitive, VCR was moderately sensitive, and ACD, BLM, VLB, CDDP, and ADM were resistant. In the human tumor xenograft system, MMC, VCR, and ADM showed tumor regression (++), and CDDP, VLB, BLM, 5-FU, and ACD exhibited no response (-). Two of the three drugs, which were classified as sensitive or intermediately sensitive in the HTCA, showed tumor regression (++) in the human tumor xenograft system. And four of the five drugs, which were resistant in the HTCA, exhibited no response (-) in the human tumor xenograft system. Clinically, PVB therapy (CDDP, VLB, and BLM) was applied to the present patient, but after recurrence, 5-FU + MMC therapy was applied on the basis of the results of the HTCA. In addition, ADM was added with reference to the results of the human tumor xenograft system. As a result of this therapy, the tumor growth was inhibited. It is possible from the present data that simultaneous chemosensitivity testing of the HTCA and the human tumor xenograft system implanted in nude mice is very useful when choosing sensitive anticancer drugs.     

多普勒超声检测肾血流评估窒息新生儿早期肾损害的价值

目的 探讨多普勒超声检测肾血流评估窒息新生儿早期肾损害的价值. 方法检测足月窒息新生儿75例(Apgar评分≤7分)和正常足月非窒息新生儿(对照组)20例生后第1、3、7天的血清尿素氮、肌酐、尿微量蛋白系列、尿酶,分析多普勒超声仪测量收缩期最大分流指数(Vmax)、舒张期最低流速(Vmin)并计算阻力指数(resistant index,RI),分析两组各指标改变情况.组间比较采用方差分析. 结果 (1)对照组新生儿第1天肾血流Vmax为(45.66±2.43)m/s,Vmin为(13.61±1.47)m/s,RI为0.69±0.09,生后第1、3、7天间差异无统计学意义.(2)轻度窒息组新生儿生后第1天血清肌酐为(49.81±19.72)pmol/L,尿微量白蛋白为(4.13±2.49)mg/L、转铁蛋白为(1.12±0.56)mg/L,N-乙酰-βD-葡萄糖苷酶为(10.72±2.79)U/(mmol·Cr),α1微球蛋白为(2.27±1.23)mg/L,均较对照组显著升高(P<0.05).(3)轻度窒息组新生儿生后第1天Vmax为(42.84±2.19)m/s、Vmin为(8.27±1.98)m/s,低于对照组;RI为0.79±0.04,高于对照组(P<0.05);重度窒息组的肾血流指数改变比轻度窒息组更明显.(4)Vmax和Vmin与血清尿素氮、肌酐,尿微量白蛋白、转铁蛋白及N-乙酰-βD-葡萄糖苷酶、α1微球蛋白呈负相关,RI与上述指标呈正相关.(5)生后第1天肾血流指标的阳性率显著高于尿微量蛋白系列和尿酶指标. 结论多普勒超声检测肾血流是一种无创、可重复性好、操作简单、结果快速的检测手段,对于窒息新生儿早期的肾功能评价具有良好的指导价值.     

Clinical studies on intravaginal administration of CDDP for dysplasia, carcinoma in situ and microinvasive carcinoma of the uterine cervix]

We attempted CDDP (cis-diaminedichloroplatinum) intravaginal administration by directly exposing the uterine cervix to CDDP in cases of dysplasia of the uterine cervix and cervical intraepithelial and micro-invasive carcinoma. Out of 12 patients, 7 had dysplasia of the uterine cervix (dysplasia was mild in 4, of an intermediate level in 1, 4 with mild dysplasia, 1 with and advanced in 2); 3 had carcinoma in situ, and 2 had microinvasive carcinoma. For CDDP intravaginal administration, a gauze tampon containing CDDP (5mg) was inserted into the vagina. CDDP administration was repeated daily for 10 days. The total dosage of CDDP administered was 50mg (new paragraph). During this period, vaginal cytologic examination was conducted and total plasma Pt content was determined daily for all. Following the completion of CDDP administration, the uterine cervices of those with dysplasia were histologically examined. For those with carcinoma in situ and microinvasive carcinoma, simple total hysterectomy was performed after intravaginal administration of CDDP to determine its therapeutic efficacy and the Pt concentration of the tissue; 1. In the 7 cases of dysplasia, dysplastic cell degeneration was observed 1-2 days after the start of intravaginal CDDP administration and these cells disappeared in all cases after its completion. 2. Sixteen histological sections of the resected cervical specimens from the 3 cases of carcinoma in situ showed complete disappearance of cancerous cells. 3. In the 2 cases of microinvasive carcinoma, no tumor cells were detected in one case; in the other case, tumor cells persisted in part of the resected specimen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of anticancer agents on 7, 12-dimethylbenz (a) anthracene induced rat ovarian cancer cell line (DMBA-OC-1) and human ovarian serous adenocarcinoma cell line (KOC-1S)

The antitumor activities of five anticancer drugs, at IC50 dosages cisplatin (CDDP), adriamycin (ADM), etoposide (VP-16), mitomycin C (MMC) and carboplatin (CBDCA) were studies an 7,12-dimethylbenz (a) anthracene induced rat ovarian cancer cell line (DMBA-OC-1) and a human ovarian serous adenocarcinoma cell line (KOC-1S). The IC50 dosage of anticancer drugs for DMBA-OC-1 was: CDDP 0.2 microgram/ml. ADM 0.04 microgram/ml, VP-16 3.0 microgram/ml, MMC 0.1 microgram/ml and CBDCA 10.0 micrograms/ml. The results of our study except those for MMC were parallel with those published on in vivo studies. The IC50 dosages of DMBA-OC-1 did not have enough antitumor activity for KOC-1S, whereas the original KOC-1S tumor strongly resisted the combination chemotherapy (CDDP, ADM and cyclophosphamide). Therefore, our findings suggested the possibility of the separation of multiple drug resistant clones from KOC-1S. These two cell lines had quite different antitumor activity characteristics.     

The clinical and pharmacokinetic evaluation of two-route chemotherapy with cisplatin and sodium thiosulfate in combination with angiotensin II]

Thirty-six courses of chemotherapy with cisplatin (CDDP) and sodium thiosulfate (STS) were performed in 31 patients with gynecologic cancer 2 weeks after operation under the hypertensive condition induced by angiotensin II (AT-II). One hundred-fifty mg of CDDP/body was intraperitoneally administered while the usual systolic blood pressure was increased to 130-140% by AT-II. The hypertension was maintained for 15 minutes after finishing CDDP infusion, then 8g of STS was intravenously infused immediately after the cessation of AT-II. The urinary Pt level measured 15 minutes after finishing CDDP infusion was extremely low at 1.37 +/- 0.47 micrograms/ml, in spite of the significantly high levels of plasma total Pt (7.83 +/- 0.85 micrograms/ml) and filtrable Pt (4.02 +/- 0.55 micrograms/ml). This suggests that, during renal vasoconstriction induced by AT-II, the renal blood flow as well as renal uptake of CDDP was decreased. Plasma filtrable Pt levels were measured at 15, 30, 60 and 120 minutes after intraperitoneal administration of CDDP. At 15 and 30 minutes a significantly higher blood concentration was found than in the control group (p less than 0.05). However, CDDP-induced toxicities of the bone marrow, liver, kidney and alimentary tract were not increased. The extreme vasoconstriction in the kidneys and other organs induced by AT-II might have protected these organs from the toxicities of CDDP despite the fact that STS infusion was delayed by 15 minutes after CDDP infusion. STS infused immediately after the cessation of AT-II could neutralize the CDDP preventing the occurrence of toxicities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of intra-arterial hypertensive chemotherapy with cisplatin and peplomycin in advanced cancer of the uterine cervix--suitable dose of angiotensin II determined by intra-arterial digital subtraction angiography

We have been treating advanced cancer of the cervix uteri with intra-arterial cisplatin (CDDP) and peplomycin (PEP) (injected into the bilateral internal iliac artery), combined with radiotherapy and hysterectomy. Concomitant angiotensin II (ATII) administered by intravenous drip infusion was found to double tumoral blood flow and thereby to enhance the efficiency of the intra-arterial chemotherapeutic regimen. In the present study, hypertensive intra-arterial chemotherapy utilizing ATII was administered to a small group of patients with advanced cancer of the cervix uteri while ascertaining the increase in intratumoral blood flow by intra-arterial digital subtraction angiography. The subjects were 10 patients with stage IIb or more advanced cancer of the cervix uteri. Results: A 2-fold or greater increase in tumoral blood flow was attained in those patients who showed concurrently a 1.5 fold or greater increase in mean blood pressure and an increase in mean blood pressure to 150mmHg or higher. In 2 patients, ATII infusion failed to raise blood pressure to a therapeutically adequate level. At 1 week after the treatment in question histological evidence indicated unequivocal degenerative changes and necrotic changes in tumor cells. Many plasma cells, lymphocytes + and granulocytes appeared around necrosis changed carcinoma nests.     

Cyclic high dose CAP therapy by short-stay admission for ovarian malignancies--to increase total dose of CDDP and to improve quality of life of patients

Since 1986, attempts have been made to improve the anti-cancer effect of Cisplatin (CDDP) in malignant ovarian tumor patients and their quality of life (QOL), by increasing single and total dose of CDDP and by short-stay cyclic treatment at our institution. In this study, the side effects of CDDP at high and low doses were compared and the effect on the QOL was analysed. Twenty ovarian malignant tumor patients who underwent adjuvant chemotherapy (CDDP 70 mg/m2, Adriamycin (ADR) 20 mg/m2, Cyclophosphamide (CPM) 200 mg/m2 given every 4 weeks for a total of 5 times and every 8-12 weeks thereafter for 5 times) after initial surgery were compared with non randomized control patients who received the old regimen of of our institution (CDDP 35 mg/m2, ADR 20 mg/m2, CRP 200 mg/m2, 5-FU 150 mg/m2 for 5 days given every 4 weeks for a total of 5 times without discharge from hospital). There was no significant difference between the groups in the white blood cell (WBC) count and creatinine clearance (Ccr) throughout the treatment, although a slight drop was observed after the second course in both groups. The QOL was examined by interviewing the patients on their physical and mental condition. Although the total amount of CDDP was increased from 175 mg/m2 to as much as 700 mg/m2, no severe nephrotoxicity or myelosuppression was seen and patients felt better and preserved a good QOL during a short hospital stay. These results clearly indicate the efficacy of our new regimen.     

The effect of endogenous tumor necrosis factor (TNF)-induction therapy in the model of VX-2 ovarian carcinoma in the rabbit

The rabbit ovarian carcinoma model was prepared by injecting VX-2 carcinoma into the ovary and the effects of endogenous Tumor Necrosis Factor (TNF)-induction therapy in combination with chemotherapy were studied. In this model, carcinoma metastasizes easily to the abdominal cavity, lung and liver, and resists treatment. Endogenous TNF was induced by a series of injections of OK-432 0.3KE and OK-432 3KE at 3 hour intervals (OK-OK group), or 1 x 10(10) cells of Bordetella pertussis vaccine (BPV group). Another group were sequential given a series of injections of CDDP (2mg/kg) intraperitoneally and OK-432 intravenously (an OK-OK and CDDP group). Higher activity of endogenous TNF was induced by BPV in comparison with OK-OK plus OK-OK and CDDP. Obvious hemorrhagic necrosis was observed in the implanted ovary in the BPV group. Compared with the control group, pulmonary metastasis was seen in the OK-OK and OK-OK plus CDDP groups (partial remission). These results show that the endogenous TNF induction therapy could be expected to be an effective antitumor therapy for advanced ovarian cancer.     

Treatment of 29 patients with bulky squamous cell carcinoma of the cervix with simultaneous cisplatin, 5-fluorouracil, and split-course hyperfractionated radiation therapy

Attempting to improve local disease control in bulky (greater than 8 cm) primary or recurrent pelvic tumors, 29 patients with squamous cell carcinoma of the cervix (stage II, 4; III, 10; IV, 6; recurrent, 9) were treated with concomitant chemotherapy and split-course hyperfractionated radiation therapy between April 1983 and August 1988. Cisplatin (CDDP) and 5-fluorouracil (5-FU) have been shown to be radiation enhancers; furthermore, CDDP, radiation therapy, and continuous-infusion 5-FU have elicited high local response rates in head and neck squamous cell carcinoma. A pilot study of cyclical week on/week off CDDP, continuous-infusion 5-FU, and hyperfractionated radiation therapy was developed. Radiation was administered at 116 cGy twice daily, Days 1-5, every other week for a median dose of 4600 cGy to a pelvic field, with paraaortic extension if indicated. Concomitant chemotherapy included CDDP 60 mg/m2 IV Day 1 and 5-FU 600 mg/m2 IV continuous infusion for 96 hr following CDDP infusion. Patients received a median of four cycles of combined treatment, and intracavitary or interstitial brachytherapy followed in 21 patients. Local pelvic response was achieved in 29 of 29 (100%): complete response (CR) in 19 of 29 (66%), partial response (PR) in 10 of 29 (34%). Among CR patients 10 of 19 (53%) were without evidence of disease at a mean follow-up of 29 (range 12-76) months. Five-year actuarial disease-free survival among complete responders was 65%. Of the 10 CR patients 2 failed in the pelvis, for a local control rate of 17/19 (89%). Chemotherapy-related and acute radiation morbidity was minimal but 2 patients required surgical correction of radiation injury. Aggressive combination of split-course hyperfractionated radiation therapy with radiation enhancers resulted in promising local control of bulky pelvic tumor, with an acceptable complication rate, in this otherwise very poor prognostic group of patients.     

Intermittent administration of the combination chemotherapy with cis-platin, adriamycin and cyclophosphamide (cyclic-PAC chemotherapy) for the ovarian cancers

Despite cis-platin-based combination chemotherapy with initially high response rates in advanced ovarian cancer, the overall survival rate remains unsatisfactory. This prompted us to design a new systematic approach using a combination chemotherapy consisting of cis-platin, adriamycin and cyclophosphamide (PAC), namely cyclic-PAC chemotherapy: Three-step chemotherapies consisting of 3 courses of the PAC regimen in each step were administered for 18 months to patients with Stage Ic-IV, after cytoreductive surgery and chemotherapy. In the present study, the survival rate with the cyclic-PAC chemotherapy was compared to that with short course-PAC and FAM (5-Fu, Alkylating agent and Mitomycin C) chemotherapies. The cyclic-PAC, PAC and FAM groups included 24 cases, 31 cases and 30 cases, respectively. Treatment of Stage Ic-IV diseases by cyclic-PAC improved the outcome (66% 3-year survival rate) compared to PAC and FAM groups (PAC 35% and FAM 30% 3-year survival rates), while no difference was observed between PAC and FAM. The outcome for patients with Stage III. IV was also superior for the cyclic-PAC group compared to the PAC and FAM groups (cyclic-PAC 54%, PAC 18% and FAM 13% 3-year survival rates). Cyclic-PAC chemotherapy is capable of dramatically improving the long-term survival rate of ovarian cancer patients.     

Effect, toxicity and tissue concentration in the clinical use of cis-diamminedichloroplatinum (II)

The tissue cis-diamminedichloroplatinum (II) (CDDP) concentration was measured in autopsies treated with CDDP therapy for gynecological malignancies. These cases consisted of 10 of ovarian tumor and one of choriocarcinoma. Total CDDP doses administered were from 55mg to 560mg and among them three cases were treated with more than 500mg (525mg, 555mg in ovarian cancer and 560mg in choriocarcinoma). We found moderate renal impairment with this drug by serum functional test and histopathology, although these changes did not correspond with the total doses. In liver, kidney and residual tumor measured for CDDP, the tissue concentration was highest in liver. When total doses administered were compared with the tissue concentration in liver, kidney, residual tumor and the decrease in creatinine clearance value, there were statistically significant differences only in residual tumor at p less than 0.01.     

Comparison of changes in biochemical markers of bone turnover after 6 months of hormone replacement therapy with either transdermal 17 beta-estradiol or equine conjugated estrogen plus nomegestrol acetate

OBJECTIVE: To compare changes in biochemical markers of bone turnover in postmenopausal women who received sequential discontinuous hormone replacement therapy (HRT) with either transdermal 17 beta-estradiol gel (group 1) or oral equine sulfoconjugated estrogen (group 2), plus nomegestrol acetate. PATIENTS AND METHOD: Prospective, open, randomized, controlled trial, conducted on 3 parallel groups of 106 postmenopausal women. All treated groups received estrogen therapy for 25 consecutive days every month. The estrogen used was either 1.5 mg/day of transdermal 17 beta-estradiol gel (group 1) [N = 42, average age (AA) = 51.6 years, average duration of menopause (ADM = 21.5 months)], or 0.625 mg/day of oral equine sulfoconjugated estrogen (group 2) [N = 39, AA = 51.3 years, ADM = 16.8 months]. In all cases nomegestrol acetate 5 mg/day was added for 12 consecutive days every month. The control group comprised 25 patients, [AA = 53.4 years, ADM = 33.7 months]. Two bone resorption markers: urinary cross-linked N-telopeptide and C-telopeptide of type I collagen (U-NTX/Cr, U-CTX/Cr), and a bone formation marker: serum bone specific alkaline phosphatase activity were measured before and 6 months after treatment start. RESULTS: Significant decreases from baseline values were observed for the 3 biochemical markers in both treated groups compared with control (P < 0.001). There were no significant differences in changes between the 2 treated groups for the 3 biochemical markers. The mean percentage change in the 3 biochemical markers was: from -9.3 to -45.5% in group 1, from -20.5 to -39% in group 2, and from -3.3 to 2% in control group. In group 1, the mean percentage decreases in U-CTX reached optimal threshold of bone turnover change (-45%) which is considered by the International Osteoporosis Foundation as clinically relevant because it predicts an increase in BMD greater than 3% when treatment is maintained over a long term. DISCUSSION AND CONCLUSION: Both treated groups induced a significant comparable decrease of bone turnover markers after 6 months of intervention, compared with control. The group treated with cyclic administration of transdermal 17 beta-estradiol (1.5 mg/day) and nomegestrol acetate (5 mg/day) showed a bone resorption markers decrease corresponding to the threshold of clinical relevance described in the international literature and predictive of positive BMD response in long term.