Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group.

PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P =.039), as were the median duration of overall success (OR or stable disease > or = 24 weeks; 60.1 v 49.1 weeks; P =.025), time to tumor progression (20.3 v 16.6 weeks; P =.037), and time to treatment failure (16.3 v 15.7 weeks; P =.042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P =.001). CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

Exemestane improves survival compared with megoestrol acetate in postmenopausal patients with advanced breast cancer who have failed on tamoxifen. results Of a double-blind randomised phase III trial.

Exemestane is an aromatase inactivator. 769 Postmenopausal women with advanced breast cancer who had failed on tamoxifen were randomised to exemestane or megoestrol acetate in this double-blind trial. Objective response rate was similar between treatments. Median time to progression, time to treatment failure and overall survival was significantly longer with exemestane. Drug-related withdrawals and drug-related deaths were more common with megoestrol acetate.

Sequential transurethral surgery, multiple drug chemotherapy and radiation therapy for invasive bladder carcinoma: initial report.

Forty-seven patients with muscle-invasive bladder cancer (T2-T4, Nx, M0) were treated by transurethral resection, followed by 3-4 cycles of combination chemotherapy (methotrexate 30 mg/m2 on days 1, 14; cis-platinum 100 mg/m2 on day 2; vinblastine 3 mg/m2 on days 1, 14; repeated every 21 days), and external beam irradiation (64-66 Gy to the bladder and 40 Gy to the pelvic lymphatics). Complete remission after trans urethral resection and chemotherapy was achieved in 24 out of 45 patients (53%). Cystectomy was performed in patients without complete response to transurethral resection and chemotherapy. The therapy was completed as planned in 45/47 patients. After transurethral resection, chemotherapy, and radiation therapy, biopsy proven complete response was achieved in 62% (28/45); Stage T2T3 in 67% (23/34), Stage T4 in 45% (5/11) of patients. Among 19 patients with positive biopsy findings after transurethral resection and chemotherapy, 14 underwent cystectomy. After follow-up of 4-55 months (median 23 months) 75% (34/45) are alive, 68% (31/45) have had their bladders preserved, and 53% (24/45) are free of the primary tumor. The actuarial survival of all 45 patients is 73%. Moderate nausea and vomiting during treatment were common; severe leukopenia and mucositis were observed in five patients. Late side effects such as miction disorders and diarrhea were predominantly mild. Although the observation period has been too short to allow a definitive evaluation of treatment results, we feel both from the point of bladder preservation and disease-free survival that the presented treatment approach is successful in a majority of T2T3 patients, whereas a large tumor size (T4) renders this treatment less effective.

Prognostic factors in invasive bladder carcinoma treated by combined modality protocol (organ-sparing approach).

PURPOSE: The results of bladder sparing approach for the treatment of muscle-invasive bladder cancer, using a combination of transurethral resection (TUR), chemotherapy, and radiotherapy, are encouraging. The survival of patients treated by this method is similar to the survival of patients treated by radical cystectomy. The aim of our study was to find out which pretreatment characteristics influence the survival of patients treated by organ sparing approach that would enable us to identify the patients most suitable for this type of treatment. METHODS AND MATERIALS: The prognostic value of different factors, such as age, gender, performance status, hemoglobin level, clinical stage, histologic grade, presence of obstructive uropathy, and completeness of TUR, has been studied in 105 patients with invasive bladder cancer, who received a bladder sparing treatment in the period from 1988 to 1995. They were treated with a combination of TUR, followed by 2-4 cycles of methotrexate, cisplatinum, and vinblastine polychemotherapy. In complete responders the treatment was completed by radiotherapy (50 Gy to the bladder and 40 Gy to the regional lymph nodes), whereas nonresponders underwent cystectomy whenever feasible. RESULTS: Our study has confirmed an independent prognostic value of performance status, histologic grade, and obstructive uropathy, for the disease-specific survival (DSS) of bladder cancer patients treated by a conservative approach. We believe that performance status best reflects the extent of disease and exerts significant influence on the extent and course of treatment, while obstructive uropathy is a good indicator of local spread of the disease, better than clinical T-stage. Our finding that histologic grade is one of the strongest prognostic factors shows that tumor biology also is a very important prognostic factor in patients treated by conservative approach. CONCLUSION: Patients with muscle-invasive bladder cancer who are most likely to benefit from conservative treatment approach include those with good performance status, absence of hydronephrosis, and histologic low grade transitional cell carcinoma.

Invasive bladder cancer: our experience with bladder sparing approach.

PURPOSE: Muscle-invasive bladder cancer (MIBC) is a disease associated with several unresolved therapeutic questions. Radical cystectomy still represents the most frequent treatment approach. The aim of our study was to evaluate the effect and feasibility of bladder-sparing treatment by transurethral resection (TUR) and sequential chemoradiotherapy in patients with biopsy-proven invasive bladder cancer. METHODS AND MATERIALS: After maximal TUR, 105 patients were treated with two to four cycles of methotrexate, cisplatinum, and vinblastine polychemotherapy. In complete responders, the treatment was continued by radiotherapy (50 Gy to the bladder and 40 Gy to the regional lymph nodes), whereas in nonresponders, cystectomy was performed when feasible. RESULTS: Complete response after TUR and chemotherapy was achieved in 52% of patients. After a median follow-up of 42 months, 52 of 75 patients (69%) selected for bladder preservation were without evidence of disease in the bladder. Freedom from local failure in complete responders to chemotherapy was 80% [95% confidence interval (CI), 69-91%) at 4 years. The actuarial survival of the entire group was 58% (95% CI, 47-69%), whereas the survival rate with the bladder intact was 45% (95% CI, 34-56%) at 4 years. Survival was significantly better in patients who responded to chemotherapy (79%) than in nonresponders (35%, p < 0.0001). There was no significant difference in survival between nonresponders who underwent cystectomy and nonresponders who completed treatment with radiotherapy (approximately 30% at 3 years). CONCLUSION: The present study confirms that MIBC is a heterogeneous disease, and that in more than half of patients who are affected, a bladder-sparing approach is safe. Our study has also demonstrated that in nonresponders, radical cystectomy as the treatment of choice is questionable.

Clinical evaluation of potential usefulness of CEA, CA 15-3, and MCA in follow-up of breast cancer patients.

The potential usefulness of MCA, CA 15-3 and CEA in monitoring of breast cancer patients was evaluated in 135 female patients with histologically confirmed breast cancer. The patients were classified into two groups as follows: group of patients with no evidence of disease, NED; and group of patients with progressive disease, PD. In total, 2106 measurements of CEA, CA 15-3, and MCA were performed using an enzyme immunoassay. Serum levels of all three markers in the NED group differed significantly from those of patients with PD. The observed differences in the sensitivity and specificity of CEA, CA 15-3, and MCA tests were not significant. The serum concentrations of a particular marker correlated well with the concentrations of the other two markers, except when CEA was correlated with MCA or CA 15-3 in NED group patients. The elevation of tumor markers preceded by some 7 months the clinical evidence of dissemination, and marker levels reflected at a high percentage the response to therapy in PD patients. Therefore, this clinical study confirmed that MCA, CA 15-3 and also CEA are suited to discriminate between disease and disease-free periods, and also validated the usefulness of markers for treatment response monitoring.

Phase-II clinical trial of 4'-epi-doxorubicin in metastatic solid tumors.

4'-Epi-doxorubicin, one of the analogs of doxorubicin, was shown in experimental animal tumor models to have a wide spectrum of antitumor activity. In comparison, its toxic side effects were less prominent than those of doxorubicin. Results of the first phase-I and II clinical trials in human tumors have confirmed experimental data. The aim of our study was to carry out a broad phase-II clinical trial mainly in various types of primarily chemoresistant solid tumors to obtain further information on the antitumor activity spectrum and toxicity of 4'-epi-doxorubicin. Ninety-two patients, 55 males and 37 females aged from 32 to 75 with an average age of 51 years, were available for the study. Karnofsky performance status was not less than 50. Previous chemotherapy was recorded in 33 patients. The drug was administered at doses of 40 mg/m2 i.v. daily for 2 days in the first 25 patients and, in all other patients, the dosage was increased to 50 mg/m2 i.v. daily for 2 days (100 mg/m2/cycle). The overall response was registered in 18 (seven complete, 11 partial remissions) out of 92 patients (20%). Regarding tumor types, the response was observed in 2/15 lung, 4/15 stomach, 3/14 colorectal, and 5/13 breast cancers. No response was observed in 11 patients with melanoma and five with hypernephroma. Toxicity was mild (myelosuppression, gastrointestinal toxicity, cardiotoxicity) and tolerable for the patients. On the basis of these results, we could conclude that 4'-epi-doxorubicin is an active antitumorigenic agent in breast cancer and in stomach, rectal, and small-cell lung tumors. These results justify further clinical investigation of this compound especially in combination chemotherapy treatment.

Exemestane improves survival in metastatic breast cancer: results of a phase III randomized study.

We compared the efficacy and safety of the oral aromatase inactivator exemestane (EXE) with megestrol acetate (MA) in women with metastatic breast cancer. This phase III randomized, double-blind, multicenter study was conducted in 769 postmenopausal women who had experienced tamoxifen failure. Treatment arms consisted of EXE 25 mg once daily (n=366) or MA 40 mg four times daily (160 mg daily; n=403). Peer-reviewed, intent-to-treat analyses demonstrated that EXE induced a trend toward higher rates of complete response (CR)+partial response (PR) (15.0% vs. 12.4%) and of CR+PR+stable disease (SD)=24 weeks (37.4% vs. 34.6%), but differences were not statistically significant. Statistically significant differences favoring EXE were seen in median duration of CR+PR+SD=24 weeks (60.1 vs. 49.1 weeks; P=0.025), time to tumor progression (20.3 vs. 16.6 weeks; P=0.037), time to treatment failure (16.3 vs. 15.7 weeks; P=0.042), and overall survival (not reached vs. 123.4 weeks; P=0.039). Both treatments were well tolerated, but MA was associated with more grade 3 or 4 weight gain (8% vs. 17%, P=0.001); the pain score was sim-ilar in both groups. There was a trend toward superiority in treatment-related signs and symptoms (TRSS) with EXE. There was greater improvement in the pain score and TRSS in patients achieving an objective response with EXE vs. MA. Quality of life improved or was similar for EXE in most domains. Exemestane offers an important new treatment option for postmenopausal women with hormone-responsive breast cancer.

CAP (cyclophosphamide, adriamycin, platinum) vs CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisolone) combination chemotherapy in untreated metastatic breast cancer. A preliminary report of a controlled clinical study.

The prospective controlled phase III clinical trial compared the therapeutic value of the cis-platinum - adriamycin - cyclophosphamide combination (CAP) and that of the combination of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisolone (CMFVP) in untreated metastatic breast cancer. Seventy-two patients (greater than 2 cycles) were evaluated: 36 had received CAP and 36, CMFVP. An objective response (CR + PR) to CAP combination chemotherapy was achieved in 75% of patients (27 of 36), with a high rate (42%) of complete remissions. In terms of metastatic site, the response rate appeared to be particularly high in soft tissue and visceral organ (lung, liver) metastases. In the CMFVP group, an objective response was noted in 16 of 36 patients (44%) with 19% complete remissions. Overall therapeutic response and the complete remission rate were better with CAP regimen (statistically significant; P less than 0.01). The duration of remissions was 4-16+ months (M = 12) for CAP and 2-12+ months (M = 8) for CMFVP. Toxic side-effects were more pronounced in the CAP group, particularly myelosuppression, and anemia was prevalent. Side-effects of CMFVP treatment were mild. In 11 CMFVP-resistant cases CAP was administered as second-line treatment, and an objective response was observed in 45% of cases (5 of 11). The preliminary results of this controlled trial show the advantage of the CAP combination in the treatment of metastatic breast cancer.

Combination of 5-fluorouracil, imidazole carboxamide, BCNU and prednisolone (FIB-P) as a salvage chemotherapy in heavily pretreated breast cancer patients.

The results of treatment with 5-fluorouracil, imidazole carboxamide, BCNU and prednisolone (FIB-P) salvage chemotherapy in 60 patients with heavily pretreated advanced breast cancer are presented. For most of the patients (82%) this was the third line of chemotherapy. Performance status (ECOG) was 1, 2 and 3 in respectively 13, 27, and 20 patients. Predominant metastatic sites were: soft tissue (3/60, 5%), bone (22/60, 37%), and viscera (35/60, 58%). Tumor burden (number of affected organic systems) was 1, 2 and 3 or more in respectively 18, 24 and 16 patients. Average dose intensity received was 0.74 (range, 0.47-0.98); the average number of cycles was 3.8 (range, 2-8). Objective response (CR + PR) was observed in 22 patients (1 CR, 21 PR), with a response rate of 37% (22/60). Median duration of remission was 7 months (range, 3-15). Tumor burden was the only pretreatment patient characteristic that significantly influenced the remission rate (p less than 0.10). Dose intensity significantly affected tumor response (p less than 0.05). Toxic side effects (gastrointestinal disorders, alopecia and myelotoxicity) were generally moderate and tolerable. No treatment-related death occurred. FIB-P proved to be an active salvage chemotherapy in heavily pretreated patients with advanced breast cancer.

First-line chemotherapy with cisplatin, methotrexate and vinblastine in metastatic bladder cancer.

To determine the effectiveness of combination chemotherapy with cisplatin, methotrexate and vinblastine (CMV), we treated 21 chemotherapy naive patients with metastatic transitional cell carcinoma of the bladder. Chemotherapy consisted of methotrexate (30 mg/m2 i.v. days 1 and 8), vinblastine (3 mg/m2 i.v. days 1 and 8) and cisplatin (100 mg/m2 i.v. day 2) every three weeks. Dominant metastatic sites were: soft tissues (7 patients), bone (6 patients), lung and liver (8 patients). A complete remission was achieved in 5/21 patients (24%, 95% CI 8-47%) and partial remission in 9/21 patients (43%, 95% CI 22-66%). The median duration was 6 months (2-11) and 9 months (2-26) for complete and partial remissions, respectively. The median survival for all 21 patients was 10 months. Although overall toxicity was mild, we observed myelosuppression grade IV in 2 patients, stomatitis grade III in 2 patients, cystitis grade III in 1 patient and infection grade III in 6 patients. There were no treatment-related deaths. Our data indicate that treatment with the CMV regimen is effective and that side effects are tolerable.

Cyclophosphamide, adriamycin and platinum (CAP) combination chemotherapy, a new effective approach in the treatment of disseminated breast cancer. Preliminary report.

The prospective controlled Phase III clinical trial tested the therapeutic value of the cis-platinum-adriamycin-cyclophosphamide combination (CAP), compared with the combination including cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisolone (CMFVP), in untreated metastatic breast cancer. One hundred and twenty-three patients (greater than 2 cycles) were evaluated: 61 on the CAP, and 62 on the CMFVP schedule. An objective response (CR + PR) to CAP combination chemotherapy was achieved in 72% of patients (43/61), with a high rate (36%) of complete remissions. In terms of metastatic site, the response rate appeared to be particularly high in soft tissue and visceral organ (lung, liver) metastases. In the CMFVP group, an objective response was noted in 26 of 62 patients (42%), with 16% complete remissions. The difference in overall therapeutic response - and in the complete remission rate as well - was statistically significant to the advantage of the CAP regimen (P less than 0.01). The duration of remissions was 6-28 + months (means = 14) for the CAP, and 4-15 + months (mean = 9) for the CMFVP schedule. Toxic side effects were more pronounced in the CAP group, particularly myelosuppression, with anemia prevailing. Side effects of CMFVP treatment were moderate. In 39 CMFVP previously treated cases, CAP was administered as second-line treatment, and an objective response was observed in 51% of cases (20/39). Results of this controlled trial showed the advantage of the CAP combination chemotherapy in the treatment of metastatic breast cancer.

Intrapleural application of human leukocyte interferon (HLI) in breast cancer patients with ipsilateral pleural carcinomatosis.

Seven patients with ipsilateral pleural carcinomatosis from breast cancer were treated by intrapleural application of a crude interferon-alpha (IFN-alpha) preparation (HLI). In 4 patients, previous systemic treatment had been without effect, and 3 patients had recurrence after initial remission. Pleural carcinomatosis was confirmed by cytology in 6 patients and by histology in 1 patient. HLI was given in doses of 2.2 X 10(6) IU two to six times. The effect was evaluated by cytological examination of the pleural fluid; malignant cells disappeared in all six patients who were evaluable. Pleural fluid, while not totally resolving, did not accumulate further after HLI. Disseminated tumor was present in all at the time of eventual death. No tumor was found in the pleura at autopsy of 2 patients and the pleural fluid was free of malignant cells at the time of last follow-up examination in the 4 others. These results seem to justify further investigation on larger groups of patients with better technique of application.

Selection of candidates for oral etoposide salvage chemotherapy in heavily pretreated breast cancer patients.

Metastatic breast cancer (MBC) is still in most cases an uncurable disease and the main goal of treatment is a good quality of life for these patients. Therefore it is very important to select patients who are appropriate candidates for the particular salvage chemotherapy (CT) schedule. The aim of our study was to assess treatment response to oral etoposide, and to analyze its relationship with patients' and disease characteristics. Seventy-five patients with bidimensionally measurable MBC were included into our study. For most of the patients treatment with etoposide was third-line CT regimen and most of them (90%) had been exposed to previous anthracycline-based CT. Etoposide was administered orally at a dose of 100 mg/day for 10 days every 3 weeks. The overall response rate was 37% (95% CI: 27-50%) with a median time to progression (TTP) and survival of 4.5 and 12 months, respectively. Patients with a long disease-free interval, predominant soft tissue and bone metastases, and less than three metastatic sites responded better to oral etoposide; however, a significantly better response was achieved only in those who had responded to previous CT (46 versus 19%, p=0.04), especially to anthracyclines (50 versus 17%, p=0.016). Response to previous anthracycline-based regimen was the only characteristic that significantly influenced TTP (median TTP: 7 versus 2.5 months, p=0.0066) and survival (median survival: 13.8 versus 5 months, p=0.0072). Toxic side effects were generally mild. Salvage CT with oral etoposide is an appropriate treatment for patients who respond to previous CT, particularly to anthracyclines. It combines a favorable toxicity profile with the major advantage of an oral drug administered at home.

Synovial sarcoma: a clinicopathological study of 36 cases.

Thirty-six cases of synovial sarcoma (13 biphasic and 23 monophasic) were subjected to a clinicopathologic study that included electron microscopy and immunohistochemistry. The group consisted of 21 males and 15 females ranging in age from 2 to 63 years. The majority of tumors (27 cases) were found in the hip and lower extremity. Immunohistochemical study revealed that keratin, which was detected in 92% of the biphasic and 57% of the monophasic tumors, was a more sensitive marker of epithelial differentiation than EMA or CEA. The overall 5-year survival of the patients was 64%. Male sex, older age, presence of tumor necrosis, monophasic pattern, and absence of keratin positivity had an unfavourable effect on survival but lacked statistical significance. Survival was significantly lower in patients with tumors exhibiting more than 15 mitoses per 10 HPF (P less than .02) and in those with tumors showing necrosis and a mitotic rate greater than 5 mitoses per 10 HPF (P less than .005).

A phase II trial of cardioprotection with Cardioxane (ICRF-187) in patients with advanced breast cancer receiving 5-fluorouracil, doxorubicin and cyclophosphamide.

From January 1991 to August 1993, 237 women with metastatic breast cancer were recruited into a multicentric phase II clinical trial designed to assess the cardioprotective activity of Cardioxane (ICRF-187). All patients were treated with 5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 (FDC) and Cardioxane 1000 mg/m2, in cycles repeated every 3-4 weeks. Cardiac functions were assessed at baseline by physical examination, ECG, and resting ultrasound left ventricle ejection fraction (LVEF). The same tests were repeated regularly after the 3rd, 6th, 8th cycle and every additional 100 mg/m2 of doxorubicin. At the end of the study there were 212 evaluable patients. Prior to analysis, patients were stratified according to the presence of cardiac risks at study entry. One hundred thirty-three patients (63%) bore one or more cardiac risks. The average total cumulative dose of doxorubicin administered to the group was 311 mg/m2 (range: 200-900 mg/m2). Overall response (CR + PR) was 49.5% (105/212), with 12% of patients entering complete remission. General toxicity (WHO grading) was mild and tolerable; no excessive myelosuppression or related symptoms were observed. Three patients from the risk group experienced cardiotoxicity, with an LVEF fall below 45%, and had to be removed from the study. Another 3 patients (1 from the risk group) were removed from the study due to clinically documented congestive heart failure after 200, 300 and 400 mg/m2 of doxorubicin. In our study, Cardioxane (ICRF-187) did not influence the antitumor efficacy of FDC chemotherapy, nor did concomitant administration of Cardioxane and chemotherapy result in any other or severer toxicity than that already known for this regimen. Finally, the observation that 51% of patients with preexisting cardiac risks received doxorubicin at dose range of 450-900 mg/m2 without significant clinical or laboratory signs of cardiotoxicity supports the evidence that Cardioxane provided cardiac protection offering the possibility of longer doxorubicin chemotherapy.