First-line Capecitabine Research Articles

Randomized trial of first-line docetaxel + capecitabine (XT) versus docetaxel + epirubicin (ET) for metastatic breast cancer (MBC): Efficacy results of ERASME-4/CAPEDOC-EPIDOC

1049 Background: In MBC, XT improves time to progression and overall survival (OS) vs docetaxel alone (O'Shaughnessy, 2002) and first-line capecitabine + paclitaxel shows similar efficacy to epirubicin + paclitaxel (Luck, 2007). The ERASME-4 and CAPEDOC- EPIDOC trials were designed to assess the efficacy of XT vs ET as first-line therapy for MBC. Methods: Patients (pts) with MBC and no prior chemotherapy (adjuvant therapy permitted) were randomized to 3-weekly cycles of either XT (docetaxel 75 mg/m², d1 + capecitabine 1,000 mg/m² twice daily, d1–14) or ET (docetaxel 75 mg/m², epirubicin 75 mg/m², both d1). In the ET arm, primary prevention of febrile neutropenia with hematopoietic growth factor was recommended; ET pts received capecitabine at progression. The primary endpoint was progression-free rate 6 months after randomization. The planned sample size of 106 pts (Simon 1985), gave 95% power to test a progression-free rate of 75% (XT) vs 60% (ET). Secondary endpoints included progression-free survival (...

The correlation between ERCC1 expression and outcome of chemotherapy in patients with advanced colorectal cancer (ACC): A Dutch Colorectal Cancer Group study (DCCG)

11042 Background: The excision repair cross-complementing (ERCC) gene family prevents damage to DNA caused by nucleotide excision and repair. The expression of ERCC1 mRNA is related to resistance to platinum compounds. The aim of this study was to investigate the role of ERCC1 as a predictive factor for response to treatment in patients (pts) with ACC. Methods: Paraffin embedded blocks of the primary tumor were collected from 506 pts included in the DCCG CAIRO study (Koopman M. et al. Lancet 2007). In arm A pts received sequential treatment with first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin (capox). In arm B pts received combination treatment with first-line irinotecan + capecitabine, second-line capox. ERCC1 expression was determined by immunohistochemistry, the percentage of positive tumor cell cores and the intensity of the staining were scored. Results: In 206 pts with ERCC1-negative (41%) and 300 pts with positive (59%) tumors the median overall survival (O...

Phase II trial of first-line capecitabine plus cisplatin in patients with advanced/metastatic nasopharyngeal cancer (NPC)

6033 Background: NPC is a common malignancy in Southeast Asia and is associated with a high incidence of distant metastases. Palliative chemotherapy using cisplatin (C)-based regimens is commonly u...

Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial

This prospective multicentre phase II study characterises the toxicity and activity of first-line capecitabine and oxaliplatin combination therapy (CAPOX) in advanced biliary system adenocarcinomas. Patients received oxaliplatin (130 mg m−2, day 1) plus capecitabine (1000 mg m−2 b.i.d., days 1–14) every 3 weeks. Patients were stratified prospectively into two groups based on location of the primary (gallbladder carcinoma (GBC) or extrahepatic cholangiocarcinoma (ECC) versus intrahepatic mass-forming type cholangiocarcinoma (ICC)). Sixty-five patients were evaluable. The response rate in 47 patients with GBC/ECC was 27% (4% complete responses), and in 23 patients (49%) stable disease (SD) was encountered. In 18 patients with ICC, we observed no objective responses, but 6 patients (33%) had SD. Median survival was 12.8 months (95% CI, 10.0–15.6) for patients with GBC or ECC (GBC: 8.2 months; 95% CI, 4.3–11.7; ECC: 16.8 months; 95% CI, 12.7–20.5), and 5.2 months (95% CI, 0.6–9.8) for ICC patients. In both cohorts, therapy was well tolerated. The most common grade 3–4 toxicity was peripheral sensory neuropathy (11 patients). Our data suggest that the CAPOX regimen is a well-tolerated and active treatment option for advanced ECC and GBC but might produce poorer results for ICC.

DPD is a molecular determinant of capecitabine efficacy in colorectal cancer

Capecitabine is a fluoropyrimidine-based drug that offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. The gene expressions of the pyrimidine metabolism enzymes dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and thymidylate synthase (TS) have previously been shown to be response determinants of fluoropyrimidine-based drugs in various tumors. Therefore, we investigated whether intratumoral mRNA expression levels of these genes are also associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine. The intratumoral mRNA levels of DPD, TP and TS were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. There were 20 women and 17 men with a median age of 61 years (range 49-74). The median progression-free survival was 6.7 months (95% CI, 4.8-11.6 months), with a median follow-up of 14.4 months (range 1.3-18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P=0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (<or=0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). This pilot study suggests that intratumoral gene expression levels of DPD may be useful in predicting the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data should be validated in larger and prospective clinical trials.

First-line chemotherapy with irinotecan plus capecitabine for advanced colorectal cancer

14602 Background: The effective, oral fluoropyrimidine capecitabine is increasingly replacing intravenous (IV) 5-FU/LV in colorectal cancer treatment. The aim of this study was to evaluate efficacy and safety of the combination chemotherapy with irinotecan plus capecitabine (XELIRI), in patients with advanced colorectal adenocarcinoma. Methods: Patients with advanced colorectal adenocarcinoma received a first-line chemotherapy with capecitabine (1000 mg/m2 twice daily) on days 1–14 and irinotecan (240 mg/m2) on day 1 of a 21-day cycle. Results: Twenty-eight patients were evaluable for response. Baseline characteristics: 18men, 10 women; median age 65.5 years (range, 49–73); colon cancer (71%), rectal cancer (29%). Most common metastatic sites were the liver (53.5%), lymph nodes (43%), lung (21%) and bones (18%). There were 7 partial responses (25%), 8 cases of stable disease (28.5%), and 13 cases of disease progression (46.5%). The median survival was 14 months (range, 2–28.8 months) and median progression-free survival was 7 months (range, 6- 26 months). The median number of cycles received was 7 (range, 3–15 cycles). Frequently encountered therapy-related events were leukopenia and gastrointestinal side effects including diarrhea. Conclusions: First-line capecitabine/ irinotecan is an active combination for the treatment of metastatic colorectal cancer achieving high efficacy with a good safety profile. No significant financial relationships to disclose.

First-line docetaxel (Dx) and capecitabine (Cap) in advanced head and neck cancer

16505 Background: Dx and Cap are useful drugs in head and neck cancer. Our purpose was to establish the efficacy and safety of this combination in non selected patients (pts) with advanced or metastatic (M1) head and neck cancer. Methods: : Between Apr 2005 and Nov 2006, 33 pts with squamous cell locally advanced or M1 head and neck cancer received the following chemotherapy (Ct) schedule: Dx 75 mg/m2 day 1 and Cap 950 mg/m2/12h days 2–14, every 3 weeks.30 pts (90.9%) had received previous local radiotherapy, 11 of them with concomitant Ct. Results: Mean age was 60 years old (range 46–75). M/F: 32/1. PS 0/1/2: 1/29/3. Location of disease: only local 49%; local and M1 36%; only M1 15% (Main M1 site: lung 76.5%, nodes 11.8%, bone 5.9%, soft tissue 5.9%). Mean number of Ct cycles: 4 (range 1–7). Worst hematologic toxicities per patient G3/G4 (%): neutropenia 6/39; febrile neutropenia 36/0; anemia 3/0; trombopenia 3/3. Non-hematologic toxicities G2/G3 (%): vomiting 3/3; neuropathy 6/0; asthenia 33/6; diarrhea 21/3; mucositis 33/18; nail changes 12/0; hand foot syndrome 3/12. Other events to remark: 4 pts had neumonia (2 toxic deaths), 1 pts had angor and required a different Ct schedule, 2 pts had massive hemorrage (1 exitus). There were 7 pts not evaluable for response (4 not yet evaluated, 1 early death due to massive hemorrage, 1 toxic death due to neumonia, 1 early disphagia). Among the evaluated pts, responses were: 2 CR (7.7%), 10 PR (38.5%), 9 SD (34.6%) and 5 PD (19.2%). Median TTP was 21 weeks (95%CI 17.5 - 24.2). Median OS was 39.8 weeks (95%CI 32.4 - 47.4) by Kaplan-Meier method. Conclusions: This combination appears to be active in pts with advanced or M1 head and neck cancer. Main toxicities were neutropenia, febrile neutropenia, mucositis and asthenia. Global toxicity was important with two toxic deaths documented No significant financial relationships to disclose.

Predictive Value of MSH2 Gene Expression in Colorectal Cancer Treated with Capecitabine

Purpose The objective of the present study was to evaluate the gene expression of the DNA mismatch repair gene MSH2 as a predictive marker in advanced colorectal cancer (CRC) treated with first-line capecitabine. Patients and Methods Microdissection of paraffin-embedded tumor tissue, RNA extraction, and quantitative polymerase chain reaction were performed on tumors obtained from 37 patients with advanced CRC. Results The median relative gene expression of MSH2 was 0.65 (quartiles 0.5–0.8) in nonresponders and 1.25 (quartiles 0.92–1.38) for responders ( P = 0.038). High expression of MSH2 was associated with a hazard ratio of 0.5 (95% confidence interval, 0.23–1.11; P = 0.083) in survival analysis. Conclusion The higher gene expression of MSH2 in responders and the trend for predicting overall survival indicates a predictive value of this marker in the treatment of advanced CRC with capecitabine.

Molecular determinants of capecitabine efficacy in colorectal cancer

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]

Preliminary safety of bevacizumab with first-line Folfox, Capox, Folfiri and capecitabine for mCRC—First B.E.A.Trial

3534 Background: In a phase III pivotal trial in patients (pts) with metastatic colorectal cancer (mCRC), bevacizumab (BEV) increased overall survival by 30% when added to first-line IFL chemotherapy (CT). Safety data from controlled BEV trials have been described, and indicate that certain serious adverse events (SAE), primarily gastrointestinal (GI) perforations and arterial thromboembolic events (TE) occurred more often in pts who received CT with BEV than those who received CT alone. First BEAT was opened to evaluate safety events of BEV in a broader pt population using a variety of CT regimens. Methods: First BEAT started in June 2004 and aims to enrol up to 2000 mCRC pts in 41 countries. Eligible pts starting with first-line CT (physician’s choice) are treated until progression with BEV (5mg/kg q2w [5FU based CT] or 7.5mg/kg q3w [capecitabine based CT]). SAEs include deaths, new and prolonged hospitalizations, life-threatening as well as medically significant events and are reported within 24 hours. There BEV-relatedness is assessed by investigators. Results: By Dec 20, 2005, 1915 pts had been enrolled in 40 countries. 1603/1915 pts (male 58%; median age 59 years [29% were &gt; 65 years]; PS 0–1 99%) had baseline data available for analyses. Median follow-up was 6.7 months (mean 7.3); 1509 pts had been followed-up for &gt;60 days. The most common first-line CT regimens used with BEV were FOLFOX (28%), CAPOX (17%), FOLFIRI (25%) and capecitabine (8%). Among the 1603 pts that had started treatment with BEV, 638 SAEs were reported in 394 pts (25%). 60-day mortality was 2.4%. The most common SAE were diarrhoea 2.7% and pyrexia 2.2% and were usually not attributed as related to BEV. Related SAEs were reported in 132 (8%) pts. venous TE 1.7%, pulmonary embolism 1.1%, bleeding 1.0%, GI perforation 0.9%, arterial TE 0.8%, hypertension 0.5% wound healing complications 0.3% were usually classified as related SAEs. Conclusions: In this ongoing, large community-based study, the safety profile of BEV in first line mCRC pts receiving a variety of CT regimens, namely FOLFOX, CAPOX, FOLFIRI and capecitabine, appears consistent with that observed in large phase III randomised studies. Updated safety data, including grade 3/4 CTC toxicities, will be presented. [Table: see text]

Randomised study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer, an interim safety analysis. A Dutch Colorectal Cancer Group (DCCG) phase III study

Results on overall survival in randomised studies of mono- versus combination chemotherapy in advanced colorectal cancer patients may have been biased by an imbalance in salvage treatments. This is the first randomised study that evaluates sequential versus combination chemotherapy with a fluoropyrimidine, irinotecan and oxaliplatin. A total of 820 patients were randomised between first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin (arm A) versus first-line capecitabine + irinotecan, and second-line capecitabine + oxaliplatin (arm B). The primary end point was overall survival. We present the results of an interim analysis on the safety data in the first 400 patients. In first-line the incidence of grade 3-4 diarrhoea, nausea, vomiting and febrile neutropenia was significantly higher in arm B. However, when toxicity over all lines was considered only grade 3 hand-foot syndrome occurred more frequently in arm A (12% versus 6%, respectively, P = 0.041). The incidence of cardiovascular toxicity was low. In two out of five patients with sudden death (one in arm A, four in arm B) cardiovascular risk factors were present. Both treatment arms had an acceptable safety profile. These data imply that the results on survival will be the major determinant for the selection of either strategy. Capecitabine plus irinotecan appears to be a feasible first-line treatment for patients with advanced colorectal carcinoma.

602 ORAL Preliminary safety of bevacizumab with first-line FOLFOX, CAPOX, FOLFIRI and capecitabine for mCRC — first BEATrial

602 ORAL Preliminary safety of bevacizumab with first-line FOLFOX, CAPOX, FOLFIRI and capecitabine for mCRC — first BEATrial

Dose reduced first-line capecitabine monotherapy in older and less fit patients with advanced colorectal cancer (ACRC)

3577 Background: Combination chemotherapy results in improved outcomes in trials of selected fit patients with ACRC. For older, less fit, more complicated patients, combination chemotherapy is associated with greater toxicity and less benefit. Sequential monotherapy is a reasonable option for these patients. Methods: A multicentre phase I/II trial of capecitabine (Xeloda) 2000mg/m2 d1–14 q21d was conducted in 214 patients in one or more of the following subsets: age≥65 years (167 pts), ECOG performance status ≥1 (139 pts), elevated LDH (105 pts), prior pelvic radiation (54 pts), liver enzyme abnormalities (5 pts). Results: Median age was 72 years (range 38 to 90). At a median follow-up of 7.2 months, 131 patients are alive. A median 4 and mean 6.5 cycles were given (range 1 to 33). Prior pelvic radiation required dose reduction to 1500mg/m2 for diarrhea in the 3rd cycle. Of 192 patients evaluable for toxicity, there were no grade 3/4 hematologic toxicities. Grade 3/4 toxicity occurred in 22% of patients during the first 3 cycles (8.9% hand-foot syndrome, 6.3% diarrhea, 2.6% lethargy, 2.6% dehydration, 1% abdominal pain, 0.5% stomatitis). Dose reductions were required in 14% and dose delays in 21% for medical reasons. Of 151 evaluable, response is 13%, with 77% disease control (CR+PR+SD). Median PFS was 5.1 months. Of 128 pts progressing, 77 (60%) received further chemotherapy. Median overall survival for all patients is 16.3 months. Median survival for ECOG PS 0, 1, and 2 are 18.4, 15.2 and 8.3 months (p=0.013 for 3 way comparison). Good prognostic factors included ECOG PS=0, LDH≤ULN, homocysteine≤ULN and history of prior pelvic RT. Conclusions: Lower dose capecitabine is tolerable and active in less fit patients. In a capecitabine registration trial with fit pts at 2500mg/m2, median survival was 12.8 months (Twelves, 2002). Although RR here was lower, survival was 16.3 months in this less fit population as part of a sequential monotherapy strategy. This study provides valuable information on outcomes in these under-studied patients for whom combination chemotherapy may not be preferred. Outcomes by subgroup will be reported at the meeting. Supported by research grant from Hoffmann-La Roche Ltd. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Ltd. Hoffmann-La Roche Ltd.

Results of a Phase II Open-Label Study of Capecitabine in Combination with Irinotecan as First-Line Treatment for Metastatic Colorectal Cancer

Between July 2001 and September 2002, 49 eligible patients were enrolled in an open-label phase II study to assess the efficacy and safety of first-line treatment with capecitabine/irinotecan in metastatic colorectal cancer. Patients received capecitabine (1000 mg/m2 twice daily) on days 1-14 and irinotecan (240 mg/m2) on day 1 of a 21-day cycle. Patients enrolled had a median age of 64.5 years, and 6% of patients had an Eastern Cooperative Oncology Group performance status of 2. Fifty-seven percent of patients were male. Forty-two patients were evaluable for response. There was 1 complete response (2%), 18 partial responses (43%), 20 cases of stable disease (48%), and 3 cases of disease progression (7%), for an overall response rate of 45% (95% CI, 30%-60%). The median duration of response was 5.7 months (range, 2.5-II.3 months). Median survival was 13.4 months (range, 1.2-28.8 months) and median progression-free survival was 6.2 months (range, 1.2-17.5 months). At 1 year, the estimated survival rate was 54% and the estimated progression-free survival rate was II%. The median number of cycles received was 6 (range, 1-18 cycles), and most patients (80%) required a dose modification because of diarrhea, nausea, and/or neutropenia. Grade 1/2 hand-foot syndrome occurred in 8 patients (16%). Grade 3/4 toxicities experienced by > or = 5% of patients included diarrhea (20%), neutropenia (12%), dehydration (10%), nausea (10%), anemia (6%), fatigue (6%), pain (6%), and vomiting (6%). First-line capecitabine/ irinotecan is an active combination for the treatment of metastatic colorectal cancer and feasible for use in the community-based setting. Despite significant toxicity with the regimen, the treatment was manageable with dose reduction or delay and should be investigated in phase III trials.

First-Line Capecitabine is as Effective as 5-Fluorouracil/Leucovorin in Treating Advanced Colorectal Cancer

First-Line Capecitabine is as Effective as 5-Fluorouracil/Leucovorin in Treating Advanced Colorectal Cancer