Dose-dense chemotherapy in metastatic gastric cancer with a modified docetaxel-cisplatin-5-fluorouracil regimen.

AIMS AND BACKGROUND: Previous studies have reported that in early breast cancer, lymphomas and advanced bladder cancer, dose-dense chemotherapy may be more effective than conventional treatments. In metastatic gastric cancer, chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TCF) q3w is very active, and, even though there is no international consensus on the subject, it is the regimen of choice of many European centers as first-line chemotherapy in this subset of patients. Based on these studies, we tested for the first time the feasibility and activity of an intensified dose-dense TCF regimen (q2w) modifying the 5-fluorouracil infusion with 1-folinic acid/5-fluorouracil according to the "De Gramont regimen". METHODS AND STUDY DESIGN: Patients with histologically confirmed measurable metastatic gastric cancer, ECOG performance status or=65 years received the same schedule with a dose reduction of 30%. RESULTS: Thirty-two consecutive patients were enrolled (63% male, 37% female); median age, 64 years (range, 40-81). A median of 4 cycles (range, 1-7) per patient was administered. Eleven of 32 patients (34%) required a dose reduction, mostly for hematological grade III-IV toxicity and severe asthenia. Twelve patients (38%) completed the first 4 cycles of therapy within 7 weeks, thereby finishing without delay the initially planned dose-density schedule. Twenty-eight patients were evaluated for response (1 early suspension after the first cycle because of toxicity, 3 deaths before response evaluation due to progression of disease). There were 3 complete responses (9%), 15 partial responses (47%), 7 stable disease (22%) and 3 progression of disease (9%), for an overall response rate, by intention to treat, of 56% (95% CI, 39-73). The most frequent grade 3-4 toxicities were: neutropenia (53%), thrombocytopenia (34%), anemia (16%) febrile neutropenia (22%), asthenia (38%) and diarrhea (19%). Median time to progression was 9.1 months (95% CI, 6.0-12.2); median overall survival was 10.1 months (95% CI, 8.8-12.2). CONCLUSIONS: A dose-dense TCF regimen in metastatic gastric cancer is feasible, with activity comparable to previous results achieved with epirubicin-based chemotherapy and TCF q3wk in terms of overall survival and time to progression, and deserves to be further tested in randomized phase III studies.

A pilot phase II study of chemotherapy with oxaliplatin, folinic acid, 5-fluorouracil and irinotecan in metastatic gastric cancer.

AIMS AND BACKGROUND: Previous phase II studies have reported that combinations of oxaliplatin, folinic acid and 5-fluorouracil or irinotecan, folinic acid and 5-fluorouracil are associated with good efficacy and an acceptable safety profile in metastatic gastric cancer. The aim of this study was to evaluate chemotherapy with oxaliplatin, folinic acid, 5-fluorouracil and irinotecan (COFFI regimen) in metastatic gastric cancer. METHODS: Patients received oxaliplatin (85 mg/m2 d 1), irinotecan (140 mg/m2 d 1), and L-folinic acid (200 mg/m2 d 1) followed by 5-fluorouracil bolus (400 mg/m2 d 1) and then 5-fluorouracil (2,400 mg/m2 48-h continuous infusion), every 14 days. RESULTS: Seventeen patients with metastatic gastric cancer were enrolled. Eight patients were pretreated for advanced disease. Of the 9 chemo-naïve patients, 8 were evaluated for response (1 patient was lost to follow-up): one complete response, 5 partial responses and 2 progressions of disease occurred, giving an overall response rate, at intention-to-treat analysis, of 67%. Of the 8 pretreated patients, 6 were evaluated for response (2 patients had nonmeasurable disease): one partial response, 2 disease stabilizations and 3 progressions of disease occurred, giving an overall response rate, at intention-to-treat analysis, of 12%. Median progression-free and overall survival in chemo-naïve patients were 8.2 and 10.2 months, respectively, and in pretreated patients 2.7 and 3 months. Grade 3-4 neutropenia occurred in 55% of chemo-naïve patients. Thrombocytopenia, and anemia were observed in 18% and 29%, respectively. Grade 3 nausea/vomiting occurred in 12% and grade 3 diarrhea in 6%. CONCLUSIONS: The COFFI regimen is active and well tolerated, therefore phase III studies are warranted.

Changes in microvessel density as assessed by CD34 antibodies after primary chemotherapy in human breast cancer.

BACKGROUND: Several papers have shown that quantitationof tumor angiogenesis in primary breast cancer by counting blood vessels gives an independent assessment of prognosis. The impact of chemotherapy +/- endocrine therapy on the extent of angiogenesis is unknown. METHODS: Matched pair histological tumor samples were obtained before and after primary chemotherapy from 120 breast cancer patients recruited in the same institution. The first 55 cases received cyclophosphamide, methotrexate, and 5-fluorouracil +/- Tamoxifen, whereas the subsequent 65 were submitted to single agent epirubicin. Patients underwent an incisional biopsy at diagnosis and definitive surgery on completion of three or four chemotherapy cycles. Microvessel density (MVD) was performed after staining with the CD34 monoclonal antibody. RESULTS: MVD slightly decreased after chemotherapy [median 51.26 mm(2) (range 2.33-163.1) and 44.27 mm(2) (2.33-121.16; P < 0.001)]; this small reduction neither correlated with tumor response nor with changes in Ki67 expression. MVD at baseline significantly correlated with MVD assessed at definitive surgery (Spearman r = 0.70, P < 0.001). In multivariate analysis, c-erbB2 status showed an independent role in predicting the reduction in MVD that just failed to attain the statistical significance (P = 0.08), whereas baseline parameters, such as T, N, steroid hormone receptor, bcl-2, p53, c-erbB2, and Ki67 expression, did not enter the model. CONCLUSIONS: Primary chemotherapy is able to modestly reduce the MVD in breast tumors. This small change is not biologically important, because the baseline neoangiogenesis status is not substantially changed. The change in microvessel count after chemotherapy could be potentially influenced by the c-erbB2 status.