This randomized, noncomparative, parallel-group study was designed to evaluate the pathologic complete response (pCR) rate of combined doxorubicin plus paclitaxel (AP) and doxorubicin plus ...cyclophosphamide (AC) as neoadjuvant chemotherapy in patients with previously untreated breast cancer who were unsuitable for conservative surgery.
A total of 200 patients with T2-3, N0-1, M0 disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either doxorubicin 60 mg/m(2) plus paclitaxel 200 mg/m(2) as a 3-hour infusion (AP) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (AC) every 3 weeks for 4 courses followed by surgery.
A pCR (eradication of invasive carcinoma in tumor and in axillary lymph nodes) was found in 16% and 10% of patients in the AP and AC arms, respectively, by study center pathologists, and in 8% and 6% of patients, respectively, by independent pathologists. Patients with pCRs tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (Scarff, Bloom, and Richardson scale grade 3). Breast-conserving surgery was performed in 58% and 45% of patients in the AP and AC arms, respectively. An objective clinical response was achieved in 89% of patients in the AP arm and 70% in the AC arm. At a median follow-up of 31 months, disease-free survival (DFS) was higher in patients who reached pCR versus those without pCR (91% v 70%).
The encouraging pathologic and clinical responses of patients with breast cancer after neoadjuvant chemotherapy with doxorubicin plus paclitaxel warrant additional investigation of paclitaxel in the neoadjuvant setting of breast cancer management.
The study investigated the therapeutic effects of a combination of Navelbine (vinorelbine or 5'noranhydrovinblastine; Pierre Fabre Médicament, Boulogne, France) and doxorubicin in women who had ...received no prior chemotherapy for locally advanced or metastatic breast cancer.
Ninety-seven patients with progressive and assessable advanced or metastatic breast cancer who had received no prior chemotherapy except in an adjuvant setting were entered onto the study. Eighty-nine patients were assessable for toxicity and response by World Health Organization (WHO) criteria; the other eight patients were excluded because they did not meet entry criteria or because of protocol violations. Navelbine was administered at 25 mg/m2 by 30-minute intravenous (IV) infusion on days 1 and 8, and doxorubicin at 50 mg/m2 by slow IV infusion on day 1, with each course repeated at 3-week intervals. Patients were treated for a maximum of 11 cycles or until progression or major toxicity.
Objective responses were observed in 66 of 89 assessable patients (74%; 95% confidence interval, 63% to 85%). There were nineteen (21%) complete responses (CRs) and 47 (53%) partial responses (PRs). In addition, 20 patients (22.5%) had stable disease and three (3.5%) progressed while on treatment. Responses were observed at all sites of metastatic disease. Forty-one of 58 patients with visceral disease responded (71%) and 25 of 31 with soft tissue and bone disease experienced an objective response (81%). The median duration of response was 12 months (range, 2.4 to 40.5), and the median overall survival was 27.5 months (range, 4 to 46). Neutropenia was dose-limiting, with 36 patients (41%) experiencing grade 3 or 4 toxicity. Of 727 cycles administered, there were 20 admissions (3%) for treatment of febrile neutropenia, involving 14 of 89 patients (16%). Treatment-related cardiotoxicity at grade 2 to 4 was experienced by 10% of patients and necessitated the interruption of treatment in 1.5% of cycles. Other side effects were uncommon or manageable by conventional means.
The encouraging response rates and duration achieved with this combination of Navelbine/doxorubicin under the conditions of this study deserve further randomized comparative trials with standard regimens.
Summary Purpose: A phase II–III randomised study to compare safety and efficacy of an oxaliplatin/cyclophosphamide (OXAC) combination, vs. the reference combination of cisplatin/cyclophosphamide ...(CPC), in untreated advanced ovarian cancer patients. Patients and methods: 182 patients were enrolled, of whom 177 were treated; 86 with OXAC (130 mg/m2 oxaliplatin two-hour intravenous (i.v.) infusion, 1000 mg/m2 cyclophosphamide two-hour i.v. infusion), and 91 with CPC (100 mg/m2 cisplatin one-hour i.v. infusion, 1000 mg/m2 cyclophosphamide two-hour i.v. infusion). Treatment cycles were repeated every three weeks (maximum of six cycles). Results: The main toxicities, which were significantly less severe in the OXAC arm, were myelosuppression and vomiting, including (OXAC vs CPC, % patients): grade 3–4 leuko- penia (37% vs. 56%), and anaemia (7% vs. 32%), with blood transfusions in 8% vs. 21%. In the OXAC arm. 64% of surgically assessable patients and 33% of clinically assessable patients achieved an objective response. In the CPC arm. 67% patients achieved a surgical response and 42% achieved an objective clinical response. In the OXAC and CPC arms, median progression free-survival was 13.0 and 13.3 months, and overall survival was 36.0 and 25.1 months respectively, without statistically significant difference. Conclusion: The activity and time-related parameters of the OXAC and CPC combinations in advanced ovarian cancer patients, are comparable. Combined with the better safety profile of the oxaliplatin-containing regimen, this confirms the interest of oxaliplatin combined with active new agents in this indication.
The predictive value of ERBB2 amplification/expression to doxorubicin use is controversial. Preoperative chemotherapy, followed by the pathological assessment of tumour response to treatment provide ...optimal conditions for the evaluation of the predictive value of biological parameters. We report here data on the predictive value of ERBB2 in a series of 54 cases of breast cancer treated by preoperative high-dose anthracycline-based chemotherapy. Our series consisted of 26 women presenting an inflammatory breast cancer (IBC) and of 28 women with poor prognosis primary cancer (PPPC). Patients received a total of four cycles with doxorubicin (75 mg/m
2 for IBC or 70 mg/m
2 for PPPC) and cyclophosphamide (6 g/m
2 for IBC or 1400 mg/m
2 for PPPC), every 21 days. ERBB2 expression was determined by immunohistochemistry (clone CB11) performed on a tumour biopsy taken before chemotherapy. All patients underwent surgery as a second step of treatment, and the tumour response was assessed on pathological specimens. A complete pathological response was observed in 24 of the 54 cases (44%) (95% confidence interval (CI), 31–57). Pathological complete response was positively correlated with high histological grade (
P=0.02) and with the absence of oestrogen (
P=0.003) or progesterone (
P=0.02) receptor expression. ERBB2 overexpression was found in 18 of the 54 cases (33%). A complete pathological response was observed in 33% of these cases (6/18). This figure was not significantly different from the 50% rate of complete response observed for tumours with no detectable ERBB2 expression (18/36). In this small series, ERBB2 overexpression was not a significant predictive marker of the pathological response to high-dose doxorubicin-based chemotherapy.
This study shows that subcutaneous administration of increasing doses of IL‐12, once a week, in 21 cancer patients increased the expression of cytokine genes (interferon‐gamma (IFN‐γ), tumour ...necrosis factor‐alpha (TNF‐α), IP‐10, MIG, IL‐10, IL‐4) in peripheral blood mononuclear cells even at very low doses (30 ng/kg). Surprisingly, no circulating TNF‐α or IL‐4 could be detected in the plasma of patients treated with IL‐12. However, a marked increase of soluble IL‐4 receptor was demonstrated in the plasma of five of the six patients studied, which may represent an additional mechanism by which IL‐12 inhibits the development of the Th2 response in vivo. A marked decline of IFN‐γ and IP10 induction was recorded after repeated cycles of IL‐12. In contrast, in most patients IL‐12 increased IL‐10 expression with no subsequent decrease during the course of therapy, and even an earlier peak of IL‐10 induction at the 6th cycle. In addition, a constant up‐regulation of serum soluble IFN‐γ receptor levels was observed after each cycle of IL‐12 treatment with a delayed peak compared with the IFN‐γ peak. The constant rise of IL‐10 and soluble IFN‐γ receptor during IL‐12 therapy may therefore contribute to the inhibition of IFN‐γ activity detected after repeated cycles of IL‐12. Lastly, a marked heterogeneity of cytokine induction was observed from one patient to another, which appeared to be independent of the dose of IL‐12 administered. These data may lead to a better understanding of the biological activity of IL‐12 and the in vivo mechanisms of its regulation.
We investigated the interrelationship between p53 gene alterations, MDR1 gene expression, and S-phase fraction (SPF) in breast
carcinomas treated primarily with chemotherapy or radiotherapy and ...correlated the results with patient outcome to determine
the potential clinical significance of these factors. In a consecutive series of 64 fine-needle samplings of breast cancer
patients who underwent either neoadjuvant chemotherapy (n = 53) or radiotherapy (n = 11), p53 (exons 5-9) gene alterations
by denaturating gradient gel electrophoresis and subsequent direct sequencing, MDR1 gene expression by semiquantitative reverse
transcription-PCR, and SPF by DNA flow cytometry were determined. Our results show that p53 mutations (n = 20) were significantly
associated (P = 0.01) with high SPF but not with de novo MDR1 gene expression. Most patients with wild-type p53 tumors were
found to be resistant to neoadjuvant chemotherapy. No correlation was observed between p53 mutations and the induction of
MDR1 gene expression during treatment. Although a significant correlation between shorter distant disease-free survival and
high (>/=5%) SPF (P = 0.016) was found, no correlation between distant disease-free survival and p53 status or intrinsic MDR1
gene expression was found. Poor overall survival was observed in patients with tumors with high SPF (P < 0.0004) or lacking
MDR1 gene expression (P = 0.03) before treatment, but not with p53 alterations. These data suggest that SPF remains the most
relevant biological factor for breast cancer patients treated by primary chemotherapy or radiotherapy and that p53 and MDR1
status may identify a small subset of patients that may resist therapy or pursue an aggressive course.
Background: In cancer patients, correlation between response to chemotherapy and gain in survival remains debated. We addressed this question in a multivariate analysis evaluating response to ...chemotherapy as a factor influencing survival of patients with metastatic breast cancer. Patients and Methods: From 1977 to 1992, 1430 patients included in eight consecutive prospective trials of anthracycline based first-line chemotherapy in metastatic breast cancer, were available for assessment. Median follow-up was 155 months. Results: Median survival from the date of randomisation was 24 months. Objective response rate was 63.6%. A complete response (CR) was achieved in 17% (249 patients). In a stepwise forward progression analysis objective response was the first independent prognostic factor for survival. Median survival time was 43 months for complete responders (CR). 29 months for partial responders (PR), 18 months for stable disease (SD), 5 months for progressive disease (PD). The probability of survival at 5 and 10 years was 35% and 15% for CR's and decreased to 18% and 6% for PR's. The timing of best response (at 4 or 8 months) was not related to outcome. Conclusions: Response to an anthracycline-based chemotherapy is a major independent prognostic factor in metastatic breast cancer. The use of this factor to investigate new drugs seems to be pertinent. The good prognosis of complete responders justifies further evaluation of new treatment strategies for this patient population.
Interleukin 6 and C-reactive protein (CRP) were determined prior to IL-2 therapy in sera from metastatic melanoma patients. Patients with elevated serum IL-6 (> 20 pg ml-1) and/or CRP (> 10 mg l-1) ...levels were associated with resistance to IL-2 therapy. A correlation between high serum IL-6 levels and a shorter median survival was also observed.
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