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Scientifically, it has been well established that breast-conserving treatment (BCT) in patients with breast cancer does not impair overall prognosis as compared to mastectomy. Several randomized clinical trials in the past two decades have shown that survival rates in breast cancer are stage-dependent, but independent of the extent of surgical breast tissue removal, as long as the resection margins are free of tumor infiltration. The particular importance the breast shows for female psychology and social interaction and the potential for feelings of mutilation and impaired physical integrity are another argument for carefully considering the implications connected with ablative surgical procedures. As a rational and informed basis for the shift in paradigms of invasiveness, the scientific community has felt the need to evidence the concept that local procedures have no detrimental impact on survival in such patients. Proof has been elaborated repeatedly by many investigators from different areas of the world. 1–3 The extent of tissue removed in breast cancer surgery, however, can be a predictor for local failure rate. Local relapse following mastectomy depends on tumor stage, nodal stage, and the biologic aggressiveness of the tumor and usually is an indicator of poor prognosis. By contrast, local recurrence after BCT does not necessarily have an impact on survival. In any case, the psychological and subjective burden of local failure following such interventions must never be underestimated. Therefore, BCT in general calls for adjuvant radiotherapy, although it has been shown that in a highly selected group of patients at very low risk for locoregional relapse, radiotherapy may indeed not be required. 4 This issue is under investigation in a number of prospective clinical trials. By accepted academic standards, BCT combined with adjuvant radiotherapy should be regarded as the surgical treatment of choice in patients with stage I and II breast cancer, as stated by the Consensus Development Conference as early as 1990. 5 Yet in contrast to these well-established standards, for various reasons BCT has not been fully accepted in general practice. This unfortunate discrepancy is linked to specific factors with regard to both patients and physicians. BCT rates are at considerable variance between different countries, but also within highly industrialized nations. For example, differences are reported to be marked between states in the United States. 6,7 In addition to geographic factors, the treatment level of a given hospital department is a key issue for the degree to which BCT is accepted. Women treated at university or teaching hospitals had doubled chances to have their breast preserved, while women over 70 and patients from rural areas were less likely candidates for BCT. 8 The most important factor influencing a patient’s decision on the surgical procedure to be used has proven to be the treating physician’s recommendation, which is rarely questioned in routine practice. 9 Thus, surgeons play the key role in patients’ decision-making processes. Surgeons participating in clinical trials should be particularly well educated and trained at the highest level of medical knowledge. After all, one chief argument for performing clinical trials is that quality control is given considerable attention under such circumstances. This refers to primary trial endpoints as much as general medical care for patients, including quality control measurements applied to surgical techniques and the standards of histopathology. Since 1984, the Austrian Breast & Colorectal Cancer Study Group (ABCSG) has been conducting nationwide, multicenter clinical trials in patients with stage I and II breast cancer. This framework has provided the opportunity, over one and a half decades, to investigate BCT rates in women participating in these investigations throughout Austria. To minimize potential selection bias, we selected subjects with identical basic prognostic characteristics (tumor and nodal stage, receptor status, and age) for the present analysis.

BACKGROUND Although the novel cytidine analog gemcitabine has shown superior antitumor activity compared with weekly bolus 5-fluorouracil in patients with advanced pancreatic carcinoma, further improvements of therapeutic results are warranted. The current Phase II study was initiated to investigate whether this might be achieved by dose intensification. METHODS Between August 1997 and September 1998, 43 consecutive patients with metastatic pancreatic adenocarcinoma were enrolled in this multicenter Phase II trial. Patients received 4 weekly courses of gemcitabine 2200 mg/m2 given as intravenous infusion during 30 minutes on Days 1 and 15 for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of treatment was assessed according to standard criteria, i.e., objective response, progression free survival, and overall survival, as well as by analysis of clinical benefit response (defined as ≥ 50% reduction in pain intensity, ≥ 50% reduction in daily analgesic consumption, and/or ≥ 20 point improvement in Karnofsky performance status that was sustained for ≥ 4 consecutive weeks). RESULTS Of 43 patients evaluable for objective response, 1 achieved complete and 8 partial remissions, for an overall response rate of 21% (95% confidence interval, 10–36%); 18 additional patients (42%) had stable and 16 (37%) progressive disease. The median time to progression was 5.3 months. Median survival was 8.8 months, and the probability of surviving beyond 12 months was 26.3%. Of 36 patients with tumor-related symptoms who were considered evaluable for clinical benefit response, 16 (44%) experienced significant palliation. The median time to achieve a clinical benefit response was 6 weeks, and its median duration was 27 weeks. Chemotherapy was well tolerated, with leukopenia/granulocytopenia representing the most common side effect. Gastrointestinal and other subjective toxicities were infrequent and generally mild. CONCLUSIONS Biweekly high dose gemcitabine seems to represent a safe, tolerable, and effective regimen for the palliative treatment of patients with advanced pancreatic carcinoma. Cancer 2000;88:2505–11. © 2000 American Cancer Society.

TSLC1 and DAL-1 are tumor suppressor genes involved in cell adhesion. In this study, we examined the expression and methylation pattern of these genes in breast cancer cell lines and primary breast carcinomas. TSLC1 expression was lost in 5 of 8 (63%) and DAL-1 expression was lost in 6 of 8 (75%) breast cancer cell lines, respectively. Downregulation of TSLC1 expression was observed in 43 of 50 (86%) and of DAL-1 expression in 26 of 55 (47%) primary breast carcinomas. TSLC1 methylation was found in 4 of 8 (50%) and DAL-1 methylation was observed in 6 of 8 (75%) breast cancer cell lines, respectively. Of 95 primary breast carcinomas 46 (48%) were TSLC1 methylated and 26 (27%) were DAL-1 methylated. Twenty of 43 (47%) and 10 of 26 (38%) primary breast cancer samples which showed downregulation of TSLC1 and DAL-1 expression were unmethylated for these genes. Re-expression of TSLC1 and DAL-1 was observed after treatment of BT-20 cells with 5-aza-2′-deoxycytidine and TSA. Samples from patients with grade 3 tumors were more frequently TSLC1 and TSLC1 and/or DAL-1 methylated than samples from patients with grade 1 and 2 tumors (P = 0.032, P = 0.023). Moreover, TSLC1 methylation correlated with loss of both ER and PgR staining (P = 0.011, P = 0.02). Our findings suggest that TSLC1 and DAL-1 are involved in the pathogenesis of breast cancer and are frequently inactivated by methylation.

A multicenter Phase II trial was performed to investigate the efficacy and tolerance of combined docetaxel and gemcitabine +/- recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer.Fifty-two patients participated in this trial, 51 of whom are evaluable for response. Thirty-eight patients received this combination as first-line chemotherapy, and 14 patients received this combination as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of 1500 mg/m2 gemcitabine and 50 mg/m2 docetaxel, both administered on days 1 and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of 5 microg/kg G-CSF was given.The overall response rate was 60.5% (95% confidence interval, 43.4-75.9%) in patients receiving docetaxel plus gemcitabine as first-line chemotherapy, including 4 complete responses (10.5%) and 19 partial remissions (50%); 9 patients (24%) had disease stabilization, and only 5 (13%) progressed. Second-line treatment with this regimen resulted in 6 of 14 (43%) objective responses, 5 had stable disease, and 3 progressive disease. The median time to progression was 8.5 months in the first-line setting and 6.6 months in the second-line setting, respectively. After a median follow-up time of 15 months, 36 patients (69%) are still alive with metastatic disease. Myelosuppression was commonly observed; WHO grade 3 or 4 neutropenia, however, occurred in only 15 (29%) patients and was complicated by septicemia in 2 cases; grade 3 anemia was seen in 1 patient (2%). Severe (grade 3) nonhematological toxicity except for alopecia was rarely observed and included nausea/vomiting in 3 (6%), stomatitis in 2 (4%), anaphylaxis in 2, and peripheral neuropathy, skin toxicity, and increase of liver enzymes each in one patient.Our data suggest that docetaxel and gemcitabine with and without G-CSF is an effective and fairly well-tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients exposed previously to adjuvant or palliative anthracyclines and/or alkylating agents.

BACKGROUND Oxaliplatin and raltitrexed both are active anticancer agents in the treatment of patients with advanced colorectal carcinoma: They have different mechanisms of action and toxicity profiles and have shown at least additive effects in experimental and preliminary clinical studies. The aim of this disease oriented Phase I–II study was to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLT), and the objective response rate of this combination in patients with advanced colorectal carcinoma. METHODS Between April 1998 and March 1999, 69 patients with measurable metastatic colorectal carcinoma who previously were unexposed to palliative chemotherapy were enrolled. In the Phase I part of the study, 27 patients were treated with 3-weekly courses of a fixed dose of raltitrexed (3 mg/m2 given as a 15-minute intravenous infusion) followed by a 2-hour infusion of oxaliplatin, which was escalated in consecutive cohorts of three to six patients from 85 mg/m2 to 100 mg/m2, 120 mg/m2, 130 mg/m2, and 140 mg/m2. After having defined the toxic dose, 42 additional patients were entered at one dose level below to define the therapeutic index of this combination more precisely. RESULTS In the Phase I part of the study, during the first three dose levels, only one patient each experienced DLT (Grade 3 increase in transaminases, diarrhea, and stomatitis); at level 4, two of the first six patients entered had Grade 3 neutropenic infection or peripheral neurotoxicity, whereas dose level 5 (oxaliplatin 140 mg/m2) constituted the toxic dose with three of three patients experiencing DLT (Grade 3 asthenia, transient amaurosis, and diarrhea with Grade 4 neutropenia). Externally reviewed objective responses were noted in 9 of these 27 patients (33%), and stable disease occurred in 12 patients (44.4%). Among the 42 patients who were treated subsequently at the MTD level (Phase II portion), 20 patients (47.6%) responded (95% confidence interval, 32–62.6%), and 21 patients (50%) had stable disease. Their median progression free survival was 9.0 months, and the median overall survival, with 42 patients (67%) currently alive, is > 14.5 months. Treatment tolerance at the MTD was acceptable, with only 9 of 42 patients (21%) experiencing Grade 3–4 neutropenia; Grade 3 nonhematologic adverse reactions included increase in serum transaminases in 6 patients, peripheral neuropathy in 3 patients, diarrhea in 3 patients, and both stomatitis and emesis in only 1 patient each. CONCLUSIONS The described objective response and toxicity data, which are in agreement with preliminary results of other Phase I–II studies, support the promising therapeutic potential of this combination in the treatment of patients with advanced colorectal carcinoma. Due to its substantial antitumor activity, tolerance (at the recommended MTD level), and convenient 3-weekly outpatient administration schedule, further evaluation of this regimen seems warranted. Cancer 2001;91:1264–71. © 2001 American Cancer Society.

Background. To determine the maximum tolerated dose of epirubicin for use in combination with 5-fluorouracil (5-FU) and low-dose leucovorin (LV), a Phase I–II trial was conducted in 37 patients with advanced gastric carcinoma. Methods. The doses of 5-FU (425 mg/m2) and LV (20 mg/m2), both given intravenously on days 1–5, were held constant while the dose of epirubicin was escalated in cohorts of patients (beginning dose, 50 mg/m2 on day 1). Cycles were repeated every 4 weeks. Results. Significant gastrointestinal symptoms and myelosuppression were observed infrequently at the initial dose level. At a dose of 60 mg/m2 of epirubicin on day 1, however, five of eight patients had significant mucosal toxic effects during the first cycle of therapy. In addition, two patients treated at this dose level had Grade 4 granulocytopenia with insufficient recovery to permit a second course by day 28, and one patient each had severe diarrhea and nausea and vomiting. Among 37 patients with assessable disease, there were 3 complete and 11 partial responses (response rate, 38%). Conclusions. LV modulation of 5-FU can be incorporated safely into combination chemotherapy with epirubicin and provides a relatively active regimen for treatment of disseminated gastric cancer.