Oxaliplatin, irinotecan and capecitabine (OCX) for first-line treatment of advanced/metastatic colorectal cancer: a phase I trial (SAKK 41/03).

BACKGROUND: A phase I multicentre trial was conducted to define the recommended dose of capecitabine in combination with oxaliplatin and irinotecan (OCX) in metastatic colorectal cancer. PATIENTS AND METHODS: Patients with performance status (PS) < 2 and adequate haematological, renal and liver function received oxaliplatin 70 mg/m(2) on days 1 and 15, irinotecan 100 mg/m(2) on days 8 and 22 and one of five dose levels (DL 1-5, between 800 and 1,600 mg/ m(2)) of capecitabine on days 1-29 every 5 weeks. RESULTS: 23 patients received a median of 3 cycles. 3 dose-limiting toxicities occurred (DL 1: grade 3 (G3) elevated alkaline phosphatase; DL 5: 1 patient G4 hyperglycaemia/G3 diarrhoea and 1 sudden death). The most common severe adverse event was G3 diarrhoea (13%). Severe haematotoxicity was rare. Therapy was stopped mainly due to metastasectomy or tumour progression (7 patients each). 8 patients reached a partial response. Median time to progression and overall survival (OS) were 8.0 and 21.9 months, respectively. CONCLUSIONS: The recommended capecitabine dose in this schedule is 1,400 mg/m(2) daily. The OCX regimen is well tolerated. The response rate was surprisingly low with progression-free survival (PFS) and OS within the range of a triple combination. Further studies in combination with targeted agents are warranted.

High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial.

BACKGROUND: Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma. METHODS: This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18-75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3.5 g/m(2) on day 1 (n=40) or methotrexate 3.5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice a day on days 2-3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00210314. FINDINGS: All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6-30) and 46% (31-61), respectively, (p=0.006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25-55) and 69% (55-83), respectively, (p=0.009). Grade 3-4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one). INTERPRETATION: In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone. FUNDING: Swiss Cancer League.

Early metabolic responses in temozolomide treated low-grade glioma patients.

Amino acid transport and protein synthesis are important steps of tumor growth. We investigated the time course of tumor metabolism in low-grade gliomas (LGG) during temozolomide chemotherapy, and compared metabolic responses as measured with positron emission tomography (PET) with volume responses as revealed by magnetic resonance imaging (MR). A homogeneous population of 11 patients with progressive non-enhancing LGG was prospectively studied. Imaging was done at 6-months intervals starting six months, and in a second series starting three months after treatment initiation. F-18 fluoro-ethyl-L-tyrosine (FET) uptake was quantified with PET as metabolically active tumor volume, and was compared with the tumor volume on MR. Response was defined as >or=10% reduction of the initial tumor volume. Eight patients showed metabolic responses. Already 3 months after start of chemotherapy the active FET volumes decreased in 2 patients to a mean of 44% from baseline. First MR volume responses were noted at 6 months. Responders showed a volume reduction to 31 +/- 23% (mean +/- SD) from baseline for FET, and to 73 +/- 26% for MR. The time to maximal volume reduction was 8.0 +/- 4.4 months for FET, and 15.0 +/- 3.0 months for MR. The initial metabolic response correlated with the best volume response on MR (Spearman Rank P = 0.011). Deactivation of amino acid transport represents an early indicator of chemotherapy response in LGG. Response assessment based on MR only has to be reconsidered. The time window obtained from PET may assist for individual treatment decisions in LGG patients.

Spatial heterogeneity of low-grade gliomas at the capillary level: a PET study on tumor blood flow and amino acid uptake.

UNLABELLED: Many low-grade gliomas (World Health Organization grade II) respond to chemotherapy. Cerebral blood flow (CBF) and microvessel density may be critical for drug delivery. We used PET with (18)F-fluoro-ethyl-l-tyrosine (FET) to measure the spatial distribution of the amino acid carrier, which is located at the brain capillaries, and (15)O-H(2)O to measure tumor CBF. METHODS: Seventeen patients with low-grade glioma were studied. Region-of-interest (ROI) analysis was used to quantify tumor tracer uptake, which was normalized to cerebellar uptake (tumor-to-cerebellum ratio). "Active" tumor was defined as tumor having a radioactivity concentration that was at least 110% of the cerebellar activity. This threshold provided measures of active tumor volume, global and peak tumor CBF, and (18)F-FET uptake. Trace ROIs were applied to create voxelwise profiles of CBF and (18)F-FET uptake across tumor and brain. Standard MRI sequences were used for spatial correlations. RESULTS: Fourteen of 17 tumors showed increased global CBF and (18)F-FET uptake. Active tumor volumes ranged between 3 and 270 cm(3) for (18)F-FET and between 1 and 41 cm(3) for CBF. Global (18)F-FET uptake in tumors corresponded to CBF increases (Spearman rank rho = 0.771, P < 0.01). The volumes of increased CBF and (18)F-FET uptake spatially coincided and were also correlated (rho = 0.944, P < 0.01). Trace ROIs showed that irrespective of increased (18)F-FET uptake at the tumor periphery, CBF increases were more confined to the tumor center. Within individual tumors, spatial heterogeneity was present. Particular tumors infiltrating the corpus callosum showed low CBF and (18)F-FET uptake in this tumor region. The patterns observed with PET were not reflected on MRI of the tumors, all of which presented as homogeneous non-gadolinium-enhancing lesions. CONCLUSION: Low-grade gliomas are heterogeneous tumors with regard to the distribution of amino acid uptake and CBF. Both are coupled in the tumor center. At the tumor periphery, where tumor infiltration of surrounding brain occurs, CBF may be low irrespective of increased (18)F-FET uptake. An ongoing study is investigating the effect of chemotherapy on these observations.

Capecitabine with weekly paclitaxel for advanced breast cancer: a phase I dose-finding trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD), toxicity and activity of combined weekly paclitaxel and capecitabine in patients with metastatic breast cancer. METHODS: Sixteen patients with metastatic breast cancer, of whom 15 were evaluable for toxicity and response, were enrolled in 7 Swiss centers. Paclitaxel 80 mg/m2 was given intravenously on days 1, 8 and 15. Capecitabine was administered orally on days 1 through 14 using five different dose levels. Both drugs were given in a 21-day schedule. RESULTS: Capecitabine could be administered at doses commonly used for the drug as a single agent, i.e. 1,250 mg/m2 twice daily in combination with weekly paclitaxel. Hematological and other toxicities did not appear to be dose-limiting; however, significant skin and nail toxicities were observed. A response or stable disease was observed in 87% of patients [13/15; exact 95% confidence interval (CI) 60-98%], with 2 complete responses, 4 partial responses (overall response rate 40%, exact 95% CI 16-68%) and 7 patients with stable disease for at least 9 weeks. CONCLUSION: The phase I evaluation of capecitabine in combination with fixed-dose weekly paclitaxel did not allow the definition of an MTD of capecitabine based on the predefined criteria. Instead, the dose for the phase II evaluation was determined based on the occurrence of toxicity in later courses and on experience with other regimens containing capecitabine. Capecitabine (1,000 mg/m2 twice daily, days 1-14, every 3 weeks) with paclitaxel (80 mg/m2 weekly) is a promising combination for advanced breast cancer now being investigated in a phase II trial.