Search

Intravenous (i.v.) vinorelbine (VRL) generally given on days 1 and 8 of an every three-week cycle in combination with paclitaxel (PTX) is an effective option for the treatment of metastatic breast cancer (MBC). In an effort to improve both patient and chemotherapy unit convenience, oral VRL was used at equivalent doses of i.v. VRL.The maximal tolerated dose (MTD) was determined during the first cycle of oral VRL given on days 1 and 8 or 15 and PTX infused over 3 h on day 1 every 3 weeks, maximum of 6 cycles. The dose of oral VRL was escalated from 60 to 80 mg/m2 in 10 mg/m2 increments. Paclitaxel was administered at 110 and then 135 mg/m2. The combination regimen was given as first-line chemotherapy of MBC. Three to six patients per cohort were treated.Twenty-two patients were treated in the first four cohorts (oral VRL/PTX): 60/110, 70/110, 80/110 and 80/135. In cohort 4, seven patients were treated, one patient being non-evaluable for MTD, three of them presented a dose-limiting toxicity (DLT) consisting of febrile neutropenia and neutropenic infection. Therefore 80/135 was the MTD. Because 36% of oral VRL administrations on day 8 were delayed to day 15 at 80/110, two additional cohorts were tested: in cohort 5, oral VRL 60 mg/m2 on days 1 and 15 and PTX 135 mg/m2 on day 1 and in cohort 6, oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1, every 3 weeks. In cohort 5, six out of eight patients had DLTs: omission of oral VRL on day 15 for five patients, grade 4 neutropenia7 days for another one. Therefore the recommended dose (RD) for further clinical testing was oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1 of an every 3-week cycle. Two of the three evaluable patients treated at the RD had a partial response. The pharmacokinetics of VRL and PTX is being analysed and will be further presented in a separate publication.This phase I study has determined the doses of oral VRL and PTX to be used in combination for the benefit of the patient and of the chemotherapy unit in term of nurse's workload. The recommended regimen of oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1 given every 3 weeks will be further tested in phase II.

Targeted therapies that are approved for metastatic colorectal cancer are divided into two groups: those affecting vascular endothelial growth factor (VEGF) known to interrupt tumor growth and metastasis (also called neo-angiogenesis), and agents that affect the tumor directly by interrupting the epidermal growth factor (EGF) and its receptor. Anti-angiogenic VEGF therapies are divided into two categories: one affecting the VEGF ligand, such as bevacizumab, and those that inhibit the VEGF receptor, such as PTK/ZK. Epidermal growth factor receptor (EGFR) therapies are divided into monoclonal antibodies that affect EGFR, such as cetuximab, and EGFR tyrosine kinase inhibitors, such as gefitinib. Both VEGF and EGFR areas of treatment have shown promising efficacy in first-line, combination therapy settings. Future targeted therapeutic strategies include gene profiling, combinations of capecitabine and oxaliplatin, with bevacizumab and/or cetuximab therapies.

Purpose To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). Patients and Methods Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m2 as a 2-hour infusion and FU 2.6 g/m2 by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m2 preceded by irinotecan 80 mg/m2 administered over 30 minutes (experimental group, n = 214). Results The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). Conclusion The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.

Therapeutic options for patients with metastatic colorectal cancer have clearly improved during the last years. The regular use of irinotecan and oxaliplatin in first- and second-line treatment led to a clear improvement of median overall survival time. For the first time a new therapeutic concept--the inhibition of tumor angiogenesis--has been realized for clinical use by combining the anti-VEGF monoclonal antibody bevacizumab with an irinotecan-based first-line therapy. The monoclonal antibody cetuximab, targeted against EGFR, offers another new and very effective therapeutic option to patients with advanced irinotecan-refractory colorectal cancer--even those who are already pretreated with oxaliplatin. Further clinical studies are going to evaluate the future role of these new molecular treatment options as part of those therapeutic possibilities which are already available and established for the treatment of colorectal cancer patients with advanced disease (such as the optimal sequencing, the role of orale fluoropyrimidine-based combination therapy with cetuximab or bevacizumab).

Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of paclitaxel and cisplatin alone, in combination and in sequence, were evaluated against established human gastric and ovarian carcinoma cell lines using 2-h drug exposure. The combination of cisplatin and paclitaxel was found to be additive or even synergistic when paclitaxel was given 24 h prior to cisplatin as demonstrated by isobologram analysis. However, when both drugs were given simultaneously or when cisplatin was given prior to paclitaxel, a strong antagonistic interaction was observed. This antagonism was evident for up to 72 h after a 2-h exposure to cisplatin. Pretreatment with cisplatin caused no alteration in [3H]paclitaxel uptake in HM2 gastric carcinoma cells, but resulted in decreased intracellular retention of paclitaxel. Since cisplatin treatment led to a reduction in cellular glutathione content in these cells and reduced levels of glutathione have been associated with protection against cytotoxicity of paclitaxel, cells were pretreated with L-buthionine sulfoximine (L-BSO). However, depletion of glutathione had no influence on the activity of paclitaxel. A significant accumulation of cells in S-phase was observed 24 h after cisplatin, which resolved after 48 h and resulted in a pronounced increase of G2M phase. These data demonstrate that the interactions of paclitaxel and cisplatin are highly schedule-dependent and applications of cisplatin simultaneously with or prior to paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols.

Over the last ten years we have witnessed a meaningful change in the treatment options of patients with metastatic colorectal cancer. However, not only does the composition of chemotherapy regimens, integrating the three anti-neoplastic agents fluoropyrimidines, irinotecan and oxaliplatin and the antibodies directed against the epidermal growth factor-receptor (EGFR) or vascular endothelial growth factor (VEGF), have to be considered, but the concepts of chemotherapy, aiming for cure in case of potential secondary resection of metastases or aiming for palliation, also provide challenges. Therefore, it does not come as any surprise that clinicians experience difficulties in defining a standard of care for their patients.

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

The purpose of this trial was to examine the feasibility of intensive, sequential chemo- and radiochemotherapy followed by surgery in patients with locally advanced carcinomas of the lower oesophagus and the gastro-oesophageal junction (GO junction). The chemotherapy consisted of two courses of 6 weekly administrations of 5-fluorouracil (5-FU) (2.0 g/m2, 24 h infusion) and folinic acid (FA) (500 mg/m2, 2 h infusion) combined with twice weekly cisplatin (50 mg/m2, 1 h infusion). Irradiation of 30 Gy was given concurrently with one course of cisplatin and etoposide. 25 patients with locally advanced (T3-T4 NX M0) squamous cell or adenocarcinoma of the lower oesophagus and GO junction were included and evaluated. Toxicity was usually mild to moderate (WHO grade 1 and 2) with mucositis as the most important side-effect of the pre-operative treatment. Of the patients, 94 and 88% completed the chemo- and radiochemotherapy according to the protocol, respectively. A major response (=partial remission with subjective improvement) to chemotherapy was achieved in 6/10 patients with squamous cell carcinoma and 10/15 with adenocarcinoma. 19 patients had subsequent surgery and complete resection was achieved in 16 (3 patients had intra-abdominal metastases observed at laparotomy). The operative mortality rate was 16% (3/19). 10 of the 16 patients with tumour resection had a pathological complete response. 15 patients (43%) remain alive at a median follow-up of 20 months and the median survival exceeds 16+ months. Our data suggest that this intensive pre-operative chemoradiotherapy programme is feasible and remarkably effective in patients with locally advanced carcinomas of the lower oesophagus or GO junction.

3558 Background: Increased angiogenesis is correlated with poor prognosis in patients with advanced metastatic colorectal cancer (CRC). PTK/ZK is a novel, oral angiogenesis inhibitor that potently inhibits all known VEGF receptor tyrosine kinases, important mediators in the formation of new blood vessels that contribute to tumor growth and metastasis. Methods: This trial determined the MTD and DLTs of once-daily oral PTK/ZK in combination with infusional 5-fluorouracil (5-FU)/leucovorin (LV) plus irinotecan (FOLFIRI) as first-line treatment in patients with metastatic CRC. PTK/ZK was administered orally once daily in escalating doses of 500, 1,000, and 1,250 mg/day to cohorts of 3–7 patients. FOLFIRI was administered q 2 weeks as irinotecan (180 mg/m2, day 1) plus LV (200 mg/m2, 2-hour infusion) and 5-FU (400 mg/m2 bolus followed by 600 mg/m2 as a 22-hour infusion) on days 1 and 2. Results: To date, 16 patients have been enrolled at 500 (n = 6), 1,000 (n = 7), and 1,250 (n = 3) mg/day. PTK/ZK was well tol...

3156 Background: EG cancer is diagnosed in more than 60% of patients (pts) in a locally advanced or metastatic stage. In this situation treatment options are limited; therefore exploration of a new therapeutic regimen is warranted. EGFR is expressed in a high proportion of gastric cancers associated with poor prognosis. Matuzumab, a humanized monoclonal anti-EGFR IgG1 antibody, inhibits ligand-mediated receptor signalling and has demonstrated antitumor activity in solid tumors. In a phase I study we evaluated the safety, tolerability, and pharmacokinetics of matuzumab in combination with standard chemotherapy in pts with advanced EG adenocarcinoma. Methods: Weekly doses of matuzumab (400 mg or 800 mg) were administered in addition to PFL (cisplatin [50 mg/m2] days 1, 15, 29, and leucovorin [500 mg/m2] and 5-fluorouracil [2000 mg/m2] days 1, 8, 15, 22, 29, 36) on a 7-week cycle up to a maximum of 3 cycles. Tumor response was assessed by endoscopy and CT/MRI in the last week of each cycle. Blood samples wer...

4036 Background: The US-Intergroup study 0116 has demonstrated a significant survival benefit for pts receiving adjuvant Rtx/CTx following complete resection of gastric cancer. The current study evaluates the feasibility, toxicity and efficacy of a novel adjuvant combined modality treatment strategy containing a 3–4-drug chemotherapy regimen (CTx) plus 5-FU-based RTx/CTx. Patients and methods: Between 12/2000 and 10/2003 96 pts were included. Treatment consisted of 2 cycles of FA 500 mg/m2 (2h) / 5-FU 2000 mg/m2 (24h) once weekly for 6 consecutive weeks, P 175 mg/m2 (3h) weeks 1 and 4 and DDP 50 mg/m2 (1h) weeks 2 and 5 or 2 cycles of FA 500 mg/m2 (2h) / 5-FU 2000 mg/m2 (24h) once weekly for 6 consecutive weeks with DDP 50 mg/m2 (1h) weeks 1,3,5. The applied regimen was individually chosen by each center. Radiation therapy with 45 Gy plus concomitantly applied 5-FU 225mg/m2/24h was scheduled in between the 2 cycles. Pts with completely resected adenocarcinoma of the stomach including a systematic D1 or D2...

3018 Background: Growth factor signaling through EGFR drives tumor proliferation, motility, angiogenic stimulation, and protects the cells from stress induced apoptosis. EMD 72000 is a humanized monoclonal anti-EGFR IgG1 antibody that blocks ligand binding, EGFR signaling, induces receptor downregulation, and potentially participates in antibody-dependent cell-mediated tumor cell killing. Methods: A phase I study was conducted to assess the safety and anti-tumor activity of EMD 72000 in 24 patients with advanced refractory gastrointestinal tumors. Antitumor activity was assessed using CT and 18FDG PET dual-modality tomography. Subjects were randomized in groups of 6 to receive absolute doses of 100, 200, 400, or 800 mg EMD 72000 weekly for 4 wks followed by treatment with 400 mg per wk until disease progression. EMD 72000 was administered by 1-hr IV infusion without routine premedication. CT and 18FDG PET images were obtained before treatment and in wks 4 and 8. Skin and tumor biopsies were obtained befor...