The addition of topotecan to carboplatin and paclitaxel as first-line therapy for advanced ovarian cancer; is it possible only with peripheral blood stem cell support?

A phase I study was performed in order to evaluate the tolerability of the combination of fixed doses of carboplatin and paclitaxel and escalated doses of topotecan as first line chemotherapy for advanced epithelial ovarian cancer. Three stage III and one stage IV patients entered the study. The dose limiting toxicity (neutropenia and thrombocytopenia) was reached at the first dose level: paclitaxel 175 mg/m2 on day 1, carboplatin AUC 5 on day I and topotecan 0.5 mg/m2 daily from day 1 to day 3. We conclude that it is not possible to add topotecan to standard regimens of carboplatin and paclitaxel without bone marrow support.

Advanced ovarian cancer patients with no evidence of disease after platinum-based chemotherapy: retrospective analysis of the role of second-look.

From 1981 to 1992, 230 previously chemotherapy-untreated epithelial ovarian cancer patients (Stages IIb-III or IV) received platinum-based polychemotherapy at our Division. In this presentation, time to progression and overall survival rates were retrospectively analyzed in 89 epithelial ovarian cancer patients (stage IIb, c - III or IV) with no clinical evidence of disease (clinical complete remission--CCR--in 26 patients with postsurgical residual tumor > or = 2 cm, and no clinical evidence of disease--NED--in 63 patients with post-surgical residual tumor < 2 cm) after first-line platinum-containing chemotherapy. After at least 6 courses of chemotherapy, 62 patients (group A) were submitted to second-look (SL) laparotomy (n=47) or laparoscopy (n=15); 27 patients (group B) did not undergo second-look surgery because of patient refusal, the surgeon's decision or clinical contro-indications to surgery. Groups A and B were comparable in terms of post-surgical residual tumor (< 2 cm: 71% vs 70%), median Performance Status (WHO: 1) and median age (56 vs 57 yrs). FIGO stage IIb, c was more frequent in group B (26% vs 18%--p=0.004). In 9/18 (50%) patients with clinical CR and in 31/44 (70%) NED patients no residual tumor was confirmed at SL (pathological CR--pCR). After a median follow-up of 10 years (range 5-16 years), 72% (64/89) of patients relapsed and 65% (58/89) died. Survival was significantly longer in patients with pCR (median survival 76 months vs 32, 29 and 16 months for patients with pPR, pNC or pPD, respectively, p=0.0001). Multivariate analysis identifies pCR as the only significant prognostic factor exerting an influence on survival after second-look laparotomy (p=0.0000). This study confirms that the second-look can provide an important prognostic evaluation in patients without evidence of disease after chemotherapy for ovarian cancer stages III-IV.

The combination of paclitaxel and carboplatin as first-line chemotherapy in patients with stage III and stage IV ovarian cancer: a phase I-II study.

The combination of paclitaxel 135 mg/m2 (24-hour infusion) and cisplatin 75 mg/m2 is now considered the standard treatment in first-line chemotherapy for stage III suboptimally debulked and stage IV ovarian cancer. Interest is focused on the possibility of evaluating the combination of paclitaxel with carboplatin, because it was found to be less nefrotoxic and less neurotoxic than cisplatin. This study seeks to determine the maximum tolerated dose and to assess the antitumor activity of the combination of a 3-hour paclitaxel infusion followed by carboplatin. Thirty-three chemotherapy-naive patients with stage III-IV epithelial ovarian cancer entered this open, nonrandomized dose-finding study. The first dose level investigated was paclitaxel 125 mg/m2 and carboplatin 250 mg/m2: the dose level progression was performed by alternatively increasing paclitaxel 25 mg/m2 and carboplatin 50 mg/m2. Cycles were repeated every 28 days. At least three patients were treated at each dose level. Overall, 233 and 224 cycles, respectively, are evaluable for nonhematologic and hematologic toxicity. Dose-limiting toxicities (febrile neutropenia and severe fatigue) were observed in two of six patients at level VIII (paclitaxel 225 mg/m2 and carboplatin 400 mg/m2) and therefore the previous dose-level (paclitaxel 200 mg/m2 and carboplatin 400 mg/m2) was considered as the maximum tolerated dose. Neutropenia (grade 3-4 in 63% of cycles), neurotoxicity (grade 2 in 37.5% and grade 3 in 9% of patients), arthromyalgias (grade 2 in 53% of patients and grade 3 in 3% of patients), and grade 3 alopecia were the most common toxicities observed. The incidence of thrombocytopenia was low (grade 3 in 4% of cycles) and no renal toxicity was observed. An objective remission was documented in 74% of 31 evaluated patients, including eight complete remissions (26%) confirmed by second-look surgery. The combination of paclitaxel 200 mg/m2 3-hour infusion followed by carboplatin 400 mg/m2 (30-minute infusion) is a safe and active regimen as first-line chemotherapy for advanced ovarian cancer.

Chemotherapy of advanced ovarian cancer.

Majority of ovarian cancer patients have advanced disease (stage III or IV) at diagnosis and the prognosis of these patients is poor in spite of aggressive surgery. Therefore chemotherapy has gained a fundamental role in the therapeutic approach of ovarian cancer. Platinum compounds in combination with alkylating agents and taxoids have the higher antitumor activity in ovarian cancer, while the role of anthracyclines remains controversial. Our 10-year experience with cisplatinum-based polychemotherapy in 196 advanced ovarian cancer patients previously untreated with chemotherapy is reported. 74 patients were treated with the combination cis-platinum and anthracyclines; 53 patients received the combination cis-platinum plus epirubicin alternated to cyclophosphamide plus 5-fluorouracil; 48 patients were treated with cis-platinum plus cyclophosphamide plus epirubicin and 21 patients were treated with the same combination with intraperitoneal administration of cisplatin. Our data confirm literature results of 55% remission rate, with 29% showing complete remissions. The median survival was 79 weeks and the overall 10-year survival was 13%. Complete responders had a median survival of 263 weeks and a 30% survival at 10 years. The main prognostic factors in our retrospective analysis were the objective remission, the size of residual tumor, the performance status and the stage. With the combination carboplatin (300-400 mg/sm) and cyclophosphamide (600 mg/sm) we observed 80% objective responses (23% complete responses) in 53 advanced ovarian cancer patients. The median overall survival in this group was 140 weeks. We carried out a phase II, non-randomized study of taxol in 54 ovarian cancer patients pretreated with platinum-compounds. The overall tolerability was good and an objective remission was observed in 47% of cases (8% complete remissions). The median survival was 68 weeks. As a consequence of our previous experience, a phase I dose-finding study with the combination carboplatin and taxol was started in our Division in 1994. Up to now, 22 chemotherapy untreated patients entered the study and the 5th dose level (taxol 175 mg/sm and carboplatin 350 mg/sm) has been completed without reaching the maximum tolerated dose. Our preliminary data suggest that the combination taxol-carboplatin is very active as the first-line chemotherapy in advanced ovarian cancer (73% objective remissions in 15 evaluated patients).

A new regimen of cisplatin, epirubicin and methotrexate (PEM-3) as primary chemotherapy for locally advanced bladder cancer.

In this phase II study, 41 patients with locally advanced urothelial bladder cancer (T2-4, N0, M0) were treated with primary chemotherapy (cisplatin, epirubicin, methotrexate: PEM-3). All the patients were assessable for response and toxicity. Clinical monitoring was performed with computerized tomography and cystoscopy. Nineteen clinical complete remissions (46%) and 10 partial remissions (24.5%) were obtained (CR + PR, 70.5%; 95% confidence interval, 57%-85%). Ten patients were considered to have clinically stable disease (24.5%), and 2 patients progressed (5%). Surgery after chemotherapy was performed in 22 cases: in 6 patients (27%) a pathologic complete response was achieved. The pathologic stage was lower than the initial clinical stage in 13 patients (59%). After a median follow-up of 3 years (range, 1-4), the median time to progression was 104 weeks. At this writing, 20 patients, 12 of which were submitted to surgery and 8 were not operated, are disease-free. The 3-year survival rate is 52%. No one had to interrupt the treatment because of toxicity. In conclusion, the PEM-3 regimen is a very active and well-tolerated regimen in locally advanced bladder cancer.

CEA, MCA, CA 15.3 and CA 549 and their combinations in expressing and monitoring metastatic breast cancer: a prospective comparative study.

Serum levels of carcinoembryonic antigen (CEA), mucin-like carcinoma-associated antigen (MCA), CA 15.3 and CA 549 were concurrently assayed in patients with metastatic breast cancer. Overall sensitivity in detecting metastatic breast cancer (201 pts) was CEA 45%, MCA 59%, CA 15.3 71% and CA 549 72% (P < 0.01). Sensitivity increased by only 6% to 8% when two or more antigens were simultaneously considered. An overall sensitivity of correlation with objective response (n = 71) was observed in the range of 53-67% (P = n.s.) in patients with abnormal baseline marker values, and in the range of 42-87% (P < 0.05) in patients with normal baseline values. The combination of two or more markers did not improve sensitivity, but decreased specificity of correlation with objective response. In conclusion, CA 15.3 and CA 549 have individually higher sensitivity in detecting metastatic breast cancer. No clinical advantage was observed for using two or more markers concurrently over CA 15.3 or CA 549 alone in the monitoring of metastatic breast cancer.

Pharmacokinetic evaluation of two different formulations of megestrol acetate in patients with advanced malignancies.

The bioequivalence of two megestrol acetate formulations, 160-mg "tablets" and 160-mg "sachets," was investigated in a single-dose, open-label, balanced-for-sequence cross-over study involving 12 advanced-cancer patients. The observed plasma megestrol-acetate time course obtained with both formulations was consistent with the literature data. The main source of variability in the pharmacokinetic parameters was intersubject variability; drug formulation played only a minor (and nonsignificant) role. The width of the 90% confidence interval of the area-under-the-curve (AUC) ratio (sachets: tablets) computed according to Schuirmann (0.9-1.4) was mainly due to the presence of a single outlier, showing an AUC ratio of 2.7. The trend to higher bioavailability of the new formulation was not significant, especially as compared with the dose-response data reported in the literature.

CA-549 serum levels in breast cancer monitoring.

CA-549 serum levels were assessed in 288 patients, 156 with early breast cancer (after surgery) and 132 with advanced breast cancer. CA-549 was abnormal (> 12 U/ml) in 25/156 patients (16%) without clinical signs of disease after surgery (median 9 U/ml), in 49/60 patients (82%) with disease in progression (P) (median 50 U/ml), in 19/27 patients (70%) with stationary disease (NC) (median 14 U/ml), in 25/33 patients (76%) with partial remission (PR) (median 18 U/ml) and in 4/12 patients (33%) with complete remission (CR) (median 9 U/ml). CA-549 serum levels correlated mainly with the extent of disease and secondarily with the prevalent metastatic site, higher values being observed in patients with visceral involvement (median 32.5 U/ml). CA-549 serum levels were also assessed in 51 patients at the start of treatment and at the time of objective evaluation: the results underline the concordance of CA-549 behavior with the clinical outcome in 71% of the cases. We conclude that CA-549 is a useful marker for monitoring breast cancer patients during the advanced stages of the disease.