Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

In this prospective randomized study, first-line treatment with the combination of cisplatin (P) and etoposide (E) was compared with the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in 140 patients. Complete remissions were obtained in 11% of 65 assessable patients on CMF and in 12% of 65 assessable patients on PE. Complete plus partial remission rates were 48% on CMF and 63% on PE (P = .08). Time to progression (median, 32 v 31 weeks), duration of response (48 v 39 weeks), and survival (75 v 76 weeks) were not different. Hematologic toxicity was significantly higher with PE, and gastrointestinal side effects were frequent with this treatment. This study demonstrated that the PE combination is effective as front-line chemotherapy. As far as response rate is concerned, a trend of superiority over CMF was observed, which was of borderline significance. Due to the lack of survival advantage and to toxicity, this combination is not recommended for routine clinical use. However, its high level of activity should be taken into account for further research.

Mature results of a prospective randomized trial comparing a three-weekly with an accelerated weekly schedule of cisplatin in advanced ovarian carcinoma.

In a retrospective analysis of a series of clinical trials by Levin and Hryniuk in 1987, the average relative dose intensity of first-line chemotherapy for advanced ovarian cancer correlated significantly with clinical response and survival, and cisplatin was the only drug for which the outcome correlated with the individual drug relative dose intensity. There was a need to test whether and to what extent this evidence would be confirmed in a prospective evaluation. In this study 101 patients with advanced ovarian carcinoma were randomized to receive the same total dose of cisplatin but at the conventional 3-weekly schedule (CTWS) (100 mg/m2 every 3 weeks for six cycles) (51 patients) or at an experimental accelerated weekly schedule (AWS) (100 mg/m2 every week for two triplets of three cycles separated by a 5-week interval) (50 patients). To benefit from a multidrug regimen at the same extent, patients in both arms sequentially received four cycles of doxorubicin and cyclophosphamide. The median follow-up period of this study is 9.7 years. In 42 and 40 patients of the two arms having evaluable response, the clinical complete response rates to cisplatin were 14% and 22% and the complete plus partial response rates were 48% and 55% in the CTWS and in the AWS arm, respectively. These differences were not statistically significant. However, the survival curves were similar during the first 2 years but clearly diverged thereafter in favor of the AWS arm (p = 0.07). At 5 years, 12% and 30% of the patients were still alive in the CTWS and in the AWS arm, respectively. Hematologic toxicity was not relevant in either arm of the study. Nonhematologic toxicity, especially ototoxicity, was substantial and significantly higher in the AWS arm. Although statistically nonsignificant, this AWS regimen of cisplatin is associated with long-term better survival compared to the CTWS regimen in advanced ovarian carcinoma. This accelerated approach administering cisplatin should be further investigated, especially in patients with low residual disease after primary surgery.

Bone marrow biopsy in the staging of small cell lung cancer.

From April 1982 to December 1987, 71 patients with small cell lung cancer entered a randomized clinical trial, and underwent bone marrow biopsy (BMB) as part of staging procedures. We identified 8 patients (11%) with bone marrow metastases, 6 with extensive disease independently of BMB, and 2 with extensive disease on the basis of the BMB only. BMB determined a change in the stage in only 3% (2/71) of the cases. No differences were found in the hematological parameters of the patients with or without bone marrow metastases. The median survival of the patients with bone marrow involvement was the same (41 weeks) as those with extensive disease but without bone marrow involvement. We conclude that unilateral BMB without aspiration detects a substantial proportion of bone marrow metastases in patients with extensive disease. This fact does not worsen the prognosis. A small proportion of patients with apparently limited disease has bone marrow involvement. The technique therefore contributes, to a small extent, to the definition of the clinical stage of the disease. However, bone marrow involvement is an important data of natural history, and therefore new methods to better assess this peculiar site of the disease are needed.

Combination therapy with platinum and etoposide of brain metastases from breast carcinoma.

Twenty-two consecutive patients with brain metastases from breast carcinoma were treated with a combination of platinum (100 mg/m2 day 1) and etoposide (100 mg/m2 days 4, 6, 8) every three weeks. Five (23%) achieved a complete response (CR) while 7 (32%) obtained a partial response (PR) for an overall response rate of 55%. The 95% confidence interval for combined CR and PR was 34-76%. Five patients received brain irradiation after reaching the maximum degree of objective remission by chemotherapy. Median duration of combined CR plus PR was 40 weeks (12+; 152). Median duration of survival was 58 weeks (2; 208+). Fifty-five percent of the patients were alive at one year. Our study demonstrates that this combination treatment is highly effective in the management of brain metastases from breast carcinoma.

M-VAC combination in locally advanced, locally recurrent or metastatic breast carcinoma. A phase II study.

BACKGROUND: The M-VAC combination is very effective in bladder carcinoma, as are all four drugs, as single-agent, in advanced breast carcinoma. PATIENTS AND METHODS: M-VAC was given in 27 patients, 4 with locally advanced breast carcinoma, 3 with local recurrence and 20 with distant metastases. The median age was 51 (range 25; 70). Eleven of the 20 patients with metastatic disease has been previously treated with a different chemotherapy. RESULTS: 15 of 26 evaluable patients responded, with 9 (35%) complete remissions and 6 partial responses. The overall response rate (CR plus PR) was 57% (95% confidence interval 38% to 76%). In patients with metastatic disease the median duration of response was 7 months (range 4+; 36+), median time to progression 5 months (range 1; 36+) and median duration of survival 17 months (range 1; 40+). CONCLUSION: The M-VAC combination is very effective in locally advanced, locally recurrent and metastatic breast carcinoma. Further trials are warranted to evaluate whether the activity of this combination is partially schedule-dependent.

The value of bone marrow biopsy in breast cancer at time of diagnosis. A prospective study.

Bone marrow biopsies (BMB) were performed in 173 consecutive unselected breast cancer patients at the time of diagnosis to define the value of this diagnostic tool in the initial staging of mammary carcinoma. In a group of 160 patients with a negative standard staging work-up, BMB was positive in two (1%). Both of them had negative x-ray but bone scan was positive in one and doubtful in the other. Bone marrow biopsy was positive in 31% of 13 additional patients with metastatic disease and in 44% of the nine among them with radiologically involved skeleton. These results exclude that BMB is able to discover micrometastatic foci of neoplastic disease. Its positivity appears strictly correlated with that of bone x-ray and scan. Based on the results of this prospective study, BMB is not required when both bone survey and scan are negative, but could be useful in clarifying diagnostic doubts of skeletal involvement.

The value of bone marrow biopsy in breast cancer at the time of first relapse. A prospective study.

The value of bone marrow biopsy (BMB) in advanced breast cancer at the time of first relapse was studied in a prospective manner. Bone marrow biopsy was performed in 142 consecutive unselected metastatic patients: 129 at the time of first recurrence, and 13 in patients with metastases at the time of first diagnosis. Overall, BMB was positive in 32 patients (23%). In the group with negative bone x-ray, it was positive in two patients of 84 (2%); both of them had doubtful scan. In the group with positive x-ray, BMB resulted positive in 30 of 58 (52%). There was a significant correlation between number of bone segments radiologically involved and BMB positivity rate, ranging from 15% in the patients with only one, to 68% in those with more than three sites involved (P = 0.02). Patients with x-ray evidence of metastases in the pelvis had significantly higher rate of BMB positivity (67% versus 32%; P = 0.02). The median survival time from the first relapse was 153 weeks in BMB-negative cases and 149 in positive ones. Considering only the patients with demonstration of bone invasion obtained with either or both x-ray and BMB, 34/62 patients had positive BMB (55%). In these cases BMB was found more often positive in patients 50 years or younger than in patients older than 50 years (80% versus 47%; P = 0.05); the median survival time was longer, but not significantly, in BMB-positive patients than in negative ones (149 weeks versus 119; P = 0.3). The authors conclude that BMB is not required in common restaging procedure when both bone survey and scan are negative. Bone marrow biopsy results are more often positive in younger patients and survival is not negatively affected by bone marrow invasion as diagnosed by BMB.

A comparison of continuation versus late intensification followed by discontinuation of chemotherapy in advanced breast cancer. A prospective randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.).

One hundred ninety-eight postmenopausal women with metastatic breast carcinoma were entered in this study. After six induction cycles with cyclophosphamide, methotrexate and 5-fluorouracil (CMF), patients with at least stable disease were randomized to the "continuation arm" (continuation of CMF until progression) (A, 49 evaluable patients) or to the "intensification-discontinuation arm" (addition of adriamycin and vincristine to two of the three drugs of CMF for six more cycles; i.e., CMAV, CFAV, MFAV, twice; discontinuation of chemotherapy; radiotherapy to pre-study sites of disease in patients prospectively considered as candidates to receive this treatment) (B, 46 evaluable patients). After randomization, escalation of response category occurred in five patients on A (10%) and in five on B (11%). Time to progression was transiently delayed in arm B within 6 months after randomization. There were no significant differences in the overall time to progression, duration of response or survival. On arm B, after discontinuation of chemotherapy, median time to relapse was 22 weeks. This time was significantly longer in patients who were candidates for radiation therapy (36 weeks, P = 0.005), or with a disease-free interval greater than 1 year (32 weeks, P = 0.004) or who achieved complete remission (60 weeks, P = 0.0001). On arm B, three patients (7%) are still alive in complete remission in excess of three, five and six years following discontinuation of therapy. This study indicates that late intensification of chemotherapy followed by discontinuation of treatment may maintain palliation, and allow a long treatment-free period in responding patients with advanced breast carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)