Capecitabine Combination Therapy Research Articles

Efficacy and safety of camrelizumab, apatinib, and capecitabine combination therapy in advanced biliary tract cancer: a phase 2, nonrandomized, prospective study.

Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. In this phase 2, nonrandomized,prospective study, eligible patients received camrelizumab (200mg, d1, Q3W), apatinib (250mg, qd, d1-d21, Q3W), and capecitabine (1000mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in thefirst-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in thefirst-line setting. NCT04720131.

Intracranial Efficacy of Pyrotinib and Capecitabine Combination Therapy in HER2-Positive Breast Cancer with Brain Metastases.

Approximately 50% of patients diagnosed with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (BC) are estimated to develop brain metastases (BMs). This study was aimed to assess the intracranial efficacy and survival benefits of pyrotinib and capecitabine combination therapy in the treatment of BMs in patients with HER2-positive BC. A total of 56 HER2-positive BC patients with BMs were treated with 400 mg pyrotinib once daily along with 1000 mg/m2 capecitabine twice daily for 14 days in 21-day cycles. The patients were allocated into three cohorts: (1) Cohort A composed of patients with newly diagnosed BMs without prior local radiotherapy, (2) Cohort B included patients with stable post-local radiotherapy, and (3) Cohort C composed of patients with progression following local radiotherapy. The primary endpoint was the intracranial objective response rate (CNS-ORR), while secondary endpoints included intracranial disease control rate (CNS-DCR), progression-free survival (PFS), overall survival (OS), safety, as well as QoL. The observed CNS-ORR CNS-ORR of 72.73% (95% CI 51.85-86.85%) in cohort A, 55% (95% CI 34.21-74.18%) in cohort B, and 42.86% (95% CI 21.38-67.41%) in cohort C. The mPFS was 11 months, 8.4 months, and 5.2 months in cohorts A, B, and C, respectively. Diarrhea, accounting for 23.21% of all the patients, was the most common grade 3/4 adverse event related with treatments (6/22 [27.3%] in cohort A, 4/20 [20.0%] in cohort B, and 3/14 [21.4%] in cohort C). However, there were no deaths related with treatments observed. Importantly, the QoL was efficiently maintained throughout the treatment duration. Pyrotinib and capecitabine combination therapy proved significant effectiveness as well as tolerability in treating HER2-positive BC with BMs, yielding satisfactory results, especially in radiotherapy-naive population.

Efficacy Evaluation of Bevacizumab Combined with Capecitabine in the Treatment of HER2-Negative Metastatic Breast Cancer: A Meta-Analysis.

This study aims to evaluate the efficacy of bevacizumab combined with capecitabine in treating HER2-negative metastatic breast cancer through meta-analysis. We searched literature from databases, including PubMed, Web of Science, Wiley Online Library, Ovid, CNKI, and Wanfang databases, for randomized controlled trials (RCTs) of bevacizumab combined with capecitabine (experimental group) and other treatments (control group) for HER2-negative metastatic breast cancer. Retrieved articles were published from the establishment of the database to August 9, 2022. The main outcome indicators were disease progression rate (RDP), disease progression-free survival (PFS), 1-year survival rate (OSR), the occurrence of serious adverse events (SAEs), and objective remission rate (ORR). The risk of bias was assessed according to the Cochrane systematic evaluation tool. Then, the meta-analysis was carried out using Stata16.0 software, and subgroup analysis was carried out based on various intervention methods in the control group. 8 RCTs were finally included in this study, including 2470 patients with HER2-negative metastatic breast cancer. The results of meta-analysis showed that bevacizumab combined with capecitabine had no significant advantage over the control group in terms of RDP, but the results of subgroup analysis were consistent and significant (subgroup 1 (bevacizumab or chemotherapy): DR = -0.03, 95% CI (-0.14, 0.09), P = 0.01; subgroup 2 (bevacizumab plus paclitaxel therapy): DR = -0.03, 95% CI (-0.14, 0.09), P = 0.03). Furthermore, there was no statistical difference in terms of PFS of the experimental group (MD = 9.24, 95% CI (7.88, 32.67), P = 0.05). However, the subgroup analysis showed that the combination of bevacizumab and capecitabine demonstrated a more significant significance than bevacizumab or chemotherapy alone (subgroup 1: MD = 10.11, 95% CI (7.88, 12.34), P = 0.00). Compared with the control group, the experimental group had significant differences in OSR (DR = 0.07, 95% CI (-0.01, 0.15), P = 0.00) and ORR (DR = 0.07, 95% CI (-0.01, 0.15), P = 0.00). In terms of safety, the incidence of serious adverse events in the experimental group did not show a statistically significant difference (MD = 0.01, 95% CI (-0.21, 0.19), P = 0.82). When subgroup analyses were performed, the bevacizumab plus capecitabine regimen was associated with an increased incidence of serious adverse events compared with the drug alone (subgroup 1: MD = 0.02, 95% CI (-0.16, 0.20), P = 0.00) but a reduction in serious adverse events compared with the bevacizumab plus paclitaxel regimen (subgroup 2: DR = -0.01, 95% CI (-0.21, 0.19), P = 0.00). The combination therapy of bevacizumab and capecitabine can significantly improve the RDP and OSR of patients compared with the control group. The PFS and ORR of the experimental group are significantly higher than those of bevacizumab or chemotherapy alone. Still, no statistical difference was observed for these outcome indicators between two combined treatments of bevacizumab with capecitabine or paclitaxel. Although this combined treatment scheme may increase the incidence of serious adverse events compared with that of bevacizumab or chemotherapy alone, the incidence of adverse events was decreased compared with bevacizumab combined with paclitaxel. Therefore, the chemotherapy regimen for HER2-negative metastatic breast cancer in clinical practice can be selected according to the actual situation of the patients.

An investigator-initiated study of gemcitabine and capecitabine in Indian patients with unresectable or metastatic gallbladder cancer

Background: Gallbladder cancer (GBC) has a high incidence rate in the Indo-Gangetic belt and is usually presented in the unresectable advanced or metastatic stage. In this study, we evaluated the response rate and toxicities of the gemcitabine plus capecitabine (GEM-CAP)-based combination chemotherapy in unresectable or metastatic GBC patients. Subjects and Methods: This was an investigator-initiated, single-arm, prospective study conducted on unresectable or metastatic GBC patients at Jaipur, India, for 1 year. All the patients received a GEM-CAP combination chemotherapy regimen which consisted of gemcitabine 1000 mg/m2 intravenously over 30 min on days 1 and 8 and capecitabine at 800 mg/m2 orally twice a day for 14 days, administered every 21 days. The response was evaluated in terms of overall response rate (ORR), tumor control rate (TCR), and progression-free survival (PFS). Both quantitative and qualitative toxicities were assessed. Results: A total of 35 patients were enrolled, of which 3 patients were excluded due to treatment interruption. The mean age of patients was 55 (32–80) years, with the majority being female (77.14%), having an ECOG score of 1 (71.43%), and with Stage IVB disease (77.14%). The ORR was 25%, TCR was 50%, and median PFS was 4 months. Major toxicities noted were Grade I and II hematological and nonhematological toxicities, which were managed adequately. Conclusion: The combination therapy of gemcitabine and capecitabine is reasonable, feasible, and well-tolerated approach for the treatment of unresectable advanced and metastatic GBC patients, a disease that had limited treatment options.

Combination therapy of capecitabine, irinotecan, oxaliplatin, and bevacizumab as a first\u2010line treatment for metastatic colorectal cancer: Safety lead\u2010in results from the QUATTRO-II study

SummaryBackground FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.

Development and Validation of HPLC and HPTLC Methods for Therapeutic Drug Monitoring of Capecitabine in Colorectal Cancer Patients.

Capecitabine is a prodrug of 5-fluorouracil, employed as a monotherapy or combination chemotherapy agent for treatment of colorectal cancer. Combination therapy of capecitabine consists of oxaliplatin, and hence, it becomes essential to determine that co-administration does not affect its metabolism. High-performance liquid chromatography and high-performance thin-layer chromatography methods were developed and validated to determine the plasma concentration of capecitabine. In this study, blood samples from 12 patients with colorectal cancer were collected and analyzed by both methods with a reference internal standard. Two groups consisting of six patients each were formed: the first group was treated with capecitabine monotherapy, the second group with capecitabine + oxaliplatin combination therapy. The results of analysis from both the methods indicated that there is no significant drug-drug interaction. The co-administration of oxaliplatin did not affect the metabolism of capecitabine. Both assay methods were compared for their sensitivity, robustness and specificity. It was found that both the assay methods were suitable for therapeutic drug monitoring of capecitabine.

Fructus mume Extracts Alleviate Diarrhea in Breast Cancer Patients Receiving the Combination Therapy of Lapatinib and Capecitabine.

Lapatinib and capecitabine have been widely used in the therapy of breast cancer. However, long-term use of lapatinib and capecitabine often causes the most common side effect diarrhea, which limit the medicine use. Fructus mume (F. mume) has been proved to be effective to treat chronic diarrhea with few side effects. The compounds from F. mume were extracted by using an ethanol method. Extracts of F. mume (EFM) were analyzed by HPLC. We investigated the protective effects of EFM on the diarrhea caused by lapatinib and capecitabine. From March 1st, 2016 to June 1st, 2017, 208 breast cancer patients with diarrhea caused by lapatinib and capecitabine were recruited. The patients were evenly assigned into two groups: EG group (the patients took 100 mg EFM daily) and CG group (the patients took placebo daily). The effects of EFM on diarrhea and gastrointestinal symptoms were measured by a semiquantitative method seven-point Likert scale. Overall quality of life was measured by SF-36 questionnaire and Hospital Anxiety and Depression Scale (HADS). The HPLC analysis showed that there were three components in EFM, including citric acid, 5-hydroxymethylfurfural (5-HMF), and chlorogenic acid. Breast cancer types were observed by using Hematoxylin and eosin (H&E) stain. The breast cancer can be divided into leaflet, gland and fibroblast types. Patient age, skin metastases, treatment, and grade 1 diarrhea were significant risk factors associated with for grade 2 diarrhea. EFM reduced diarrhea and gastrointestinal symptoms by reducing the average scores of the diarrhea symptom and seven-point Likert scale, and improved life quality of patients significantly by improving SF-36 scores and reducing HADS scores when compared to that in the CG group after 6-week therapy and further 4-week follow-up (P < 0.05). EFM may be a potential choice for the diarrhea therapy in breast cancer patients.

Rapid symptomatic relief of HER2-positive gastric cancer leptomeningeal carcinomatosis with lapatinib, trastuzumab and capecitabine: a case report

BackgroundGastric cancer patients with widespread metastasis, especially meningeal metastases, have an extremely prognosis and limited therapeutic choices.Case presentationWe reported the case of a 39-year-old male patient with HER2-positive gastric cancer with bone and meningeal metastases. He presented with multiple bone metastases and received 3 cycles of docetaxel plus S1. However, he complained with headache and imaging examinations revealed leptomeningeal carcinomatosis. FISH revealed that tumor cells in the cerebrospinal fluid were HER-positive. Herceptin was added to the regimen, but the symptoms were not relieved, the patient suffered from dizziness and nausea. The chemotherapy regimen was switched d to lapatinib (orally at 1250 mg/day, every day), capecitabine (orally at 1000 mg/m2, bid for 2 weeks, followed by a 1-week rest interval, as 1 cycle) and Herceptin (390 mg/3 weeks). After 3 weeks of the new treatment, all the symptoms relieved. The clinical complete response was maintained for 3 months.ConclusionsLapatinib/Capecitabine combination therapy is an alternative treatment strategy for leptomeningeal carcinomatosis of HER2-positive gastric cancer in which trastuzumab and/or chemotherapy essentially has no effect.

Abstract P1-17-08: Efficacy of lapatinib and capecitabine combination therapy in brain metastases from HER-2 positive metastatic breast cancer: A systematic review and meta- analysis

Abstract Background: Brain metastases contribute to significant morbidity and mortality in breast cancer. Approximately one fourth of breast tumors overexpress the human epidermal growth factor receptor 2 (HER2) protein and are twice as likely to develop brain metastases. There are currently no systemic therapies approved. We undertook a systematic review and pooled analysis of trials to determine the efficacy of lapatinib and capecitabine combination therapy in brain metastases from HER-2 positive metastatic breast cancer (MBC). Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through December 31, 2016. Trials that utilized lapatinib and capecitabine combination therapy in brain metastases from HER-2 positive MBC were incorporated in the analysis. The pooled estimated rates were calculated using random effects model. Heterogeneity was assessed using I2 statistic. Results: A total of 513 patients with brain metastases from HER-2 positive MBC from 6 trials and a subgroup of another 4 trials were included in our analysis. Lapatinib and capecitabine therapy was used as second-line treatment in 9 studies (n= 468) and as first-line treatment in the LANDSCAPE study (n= 45). Three studies were retrospective evaluations of randomized trials and the rest were phase 2 trials. CNS objective response rate (ORR) was 26% (95% CI: 19 – 33, I2: 65.9%). Complete response (CR) rate was 1% (95% CI: 0 - 2, I2: 0.0%) and partial response (PR) rate was noted at 24% (95% CI: 17- 31, I2: 66.1%). Stable disease (SD) occurred in 37% (95% CI: 29- 45, I2: 66.6%) and progressive disease (PD) in 19% (95% CI: 12- 25, I2: 66.5%). The first line LANDSCAPE study had the highest PR (49%) and ORR (53%) without a significant impact on CR rate; PD was 7%. Conclusion: Brain metastases in breast cancer is an area of urgent unmet need. Our meta-analysis showed that lapatinib/capecitabine therapy had some first line or second line activity in brain metastases from HER-2 positive MBC. Nevertheless, further randomized controlled trials are required in this patient population. Citation Format: Thein KZ, Zaw MH, Yendala R, Igid HP, Chai-Adisaksopha C, Hardwicke F, Awasthi S, Radhi S. Efficacy of lapatinib and capecitabine combination therapy in brain metastases from HER-2 positive metastatic breast cancer: A systematic review and meta- analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-17-08.

18F]fluorothymidine PET Informs the Synergistic Efficacy of Capecitabine and Trifluridine/Tipiracil in Colon Cancer.

In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) PET as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [3H]FLT uptake after 5-fluorouracil treatment in vitro and [18F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts (n = 10-12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine in vitro as well as the sequential combination of oral capecitabine (30-360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models (n = 6-10 per group). We observed significant increases in [3H]FLT uptake in all cell lines and [18F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [18F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition (ρ = -0.81, P = 0.02). The effects of these combinations were synergistic in vitro A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [18F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [18F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil. Cancer Res; 77(24); 7120-30. ©2017 AACR.

A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic adenocarcinoma.

TPS471 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Recent advances with fluorouracil in combination with oxaliplatin and irinotecan (FOLFIRINOX) and nab-paclitaxel combined with gemcitabine (AG) have improved survival in patients with PDAC. A fluorouracil-based regimen is recommended for patients who progress after a gemcitabine-based regimen. Tosedostat is an oral aminopeptidase inhibitor shown to have anti-proliferative effects in malignancies. Aminopeptidase inhibitors disrupt the cleavage of amino acids from peptides downstream of proteasomal degradation, preventing the recycling of amino acids needed for new protein synthesis. This leads to intracellular depletion of amino acids, resulting in a cellular stress response known as the amino acid deprivation response, which leads to apoptosis. Because pancreatic cancer cells frequently upregulate expression of these aminopeptidases, aminopeptidases inhibitors hold therapeutic promise. Methods: This is a single institution phase I/II open-label trial to evaluate the safety and tolerability of tosedostat plus capecitabine in patients with metastatic PDAC that have progressed after a gemcitabine-based regimen. The phase I part will be conducted in a dose de-escalation fashion, with two planned dose levels of tosedostat (120mg or 60mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one patient in the tosedostat (120 mg) cohort experiences a dose limiting toxicity (DLT), then 6 more patient will be enrolled to the tosedostat (60 mg) cohort. A total of 36 patients will be enrolled in the phase II portion. Primary objective of the phase I portion is to determine the maximum tolerated dose and DLTs of tosedostat and capecitabine combination therapy. Primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives are to determine the overall response rate, time-to-progression, overall survival and CA 19-9 response. Exploratory objectives are to explore the predictive molecular biomarkers for treatment response and to explore the prognostic biomarkers. Clinical trial: NCT02352831. Clinical trial information: NCT02352831.

Structural Uncertainty of Markov Models for Advanced Breast Cancer: A Simulation Study of Lapatinib.

To examine the impact of structural uncertainty of Markov models in modeling cost-effectiveness for the treatment of advanced breast cancer (ABC). Four common Markov models for ABC were identified and examined. Markov models 1 and 2 have 4 health states (stable-disease, responding-to-therapy, disease-progressing, and death), and Markov models 3 and 4 only have 3 health states (stable-disease, disease-progressing, and death). In models 1 and 3, the possibility of death can occur in any health state, while in models 2 and 4, the chance of dying can only occur in the disease-progressing health state. A simulation was conducted to examine the impact of using different model structures on cost-effectiveness results in the context of a combination therapy of lapatinib and capecitabine for the treatment of HER2-positive ABC. Model averaging with an assumption of equal weights in all 4 models was used to account for structural uncertainty. Markov model 3 yielded the lowest incremental cost-effectiveness ratio (ICER) of $303,909 per quality-adjusted life year (QALY), while Markov model 1 produced the highest ICER ($495,800/QALY). At a willingness-to-pay threshold of $150,000/QALY, the probabilities that the combination therapy is considered to be cost-effective for Markov models 1, 2, 3, and 4 were 14.5%, 14.1%, 21.6%, and 17.0%, respectively. When using model averaging to synthesize different model structures, the resulting ICER was $389,270/QALY. Our study shows that modeling ABC with different Markov model structures yielded a wide range of cost-effectiveness results, suggesting the need to investigate structural uncertainty in health economic evaluation. When applied in the context of HER2-positive ABC treatment, the combination therapy with lapatinib is not cost-effective, regardless of which model was used and whether uncertainties were accounted for.

Efficacy and safety of cisplatin plus capecitabine for patients with metastatic triple negative breast cancer progressing after anthracycline and taxane treatment

To evaluate the efficacy and safety of cisplatin and capecitabine combination (XP) therapy for patients with metastatic triple negative breast cancer (TNBC) progressing after anthracycline and taxane treatment. Twenty-nine metastatic TNBC patients were prospectively enrolled to receive capecitabine (1, 000 mg/m(2) twice daily on days 1-14) and cisplatin (75 mg/m(2) on day 1) , repeated every 3 weeks. With a median of 6 cycles of XP, all 29 patients were evaluable for response, including 18 PR (62.1%), 6 SD (20.7%), 5 PD (17.2%) and no CR. The response rate was 62.1%. Patients with earlier stage at diagnosis (stage I to IIIA), longer post-operative disease free survival (>2 years) and less metastatic sites (≤ 3) obtained significantly higher response rate than patients with later stage at diagnosis (stage IIIB to IV), shorter post-operative disease free survival (≤ 2 years) and more metastatic sites (>3). The leading side effects were grade 1/2 gastrointestinal and hematological toxicities. Grade 3/4 toxicities included neutropenia (34.5%), leukocytopenia (31.0%), anemia (6.9%), thrombocytopenia (3.4%), nausea/vomiting (20.7%), stomatitis (3.4%), and hand-foot syndrome (3.4%). Cisplatin and capecitabine combination therapy is an active and well-tolerated doublet treatment in metastatic TNBC patients progressing after anthracycline and taxane treatments.

The study of efficacy and safety of chemotherapy plus bevacizumab with oxaliplatin stop-and-go strategy in first-line treatment for metastatic colorectal cancer.

761 Background: In metastatic colorectal cancer (mCRC), the benefit of the molecular targeted drugs added to chemotherapy has been reported and a combination therapy of capecitabine (CAP) and oxaliplatin (CapeOX) plus bevacizumab (BEV) is an established first-line therapy for mCRC. However, the management of the cumlateve neurotoxicity of oxaliplatin still remains. We evaluated the efficacy and safety of CapeOX plus BEV with oxaliplatin stop and go strategy. Methods: Two prospective clinical trials of previously untreated unresectable mCRC were analyzed. Fifty four patients were treated with CapeOX plus BEV with oxaliplatin stop and go strategy (CCOG-0902). They were treated 4 cycles of CapeOX plus BV therapy followed by maintenance therapy of 8 cycles of Capecitabine plus BV and oxaliplatin reintroduction was scheduled after maintenance therapy or upon tumor progression. On the other group, forty seven patients were treated with mFOLFOX6 plus BEV (CCOG-0801). Progression free survival (PFS), overall survival (OS), response rate (RR), disease control rate (DCR), relative dose intensity (RDI), and frequency of peripheral sensory neuropathy (PSN) were evaluated. Results: Patient characteristics were balanced between the two groups. The median RDI of oxaliplatin in CCOG-0902 group was significantly higher, 92% than in CCOG-0801 group, 80%. RR and DCR were 61.5% and 96.3% respectively, in CCOG-0902 group, compared with 61.7% and 89.4% respectively, in CCOG-0801 group. Median PFS was 13.6 and 30.5 months, respectively, compared with 11.7 and 31.6 months, respectively, in CCOG-0801 group (p=not significant). The frequency of peripheral sensory neuropathy (PSN) was 19.0% (&gt;Grade3: 1.9%) of patients in CCOG-0902 group compared with 72.3% (&gt;grade 3: 17.0%) in CCOG-0801 group. Conclusions: CapeOX plus BV with oxaliplatin stop and go strategy could have same efficacy as continuing oxaliplatin with avoiding PSN. Clinical trial information: UMIN000006478.

Haematologic Parameters in Metastatic Colorectal Cancer Patients Treated with Capecitabine Combination Therapy

The standard treatment in the metastatic colorectal cancer consists of 5-FU based infusional regimens. However, with oral fluoropyrimidines, equal tumor responses may be obtained. Capecitabine causes macrocytosis of the cells by inhibition of DNA synthesis. In this context, a relationship was found between mean corpuscular volume (MCV) and response to therapy in breast cancer patients treated with Capecitabine, but whether this relationship also pertains in colorectal cancer has not been established. A total of 102 metastatic colorectal cancer patients treated with a oxaliplatin (XELOX) ±Bevacizumab combination were retrospectively evaluated. Patients were randomized into three groups. Hematological parameters (MCV, MPV, PCT, PLT, NLR) were recorded retrospectively, before treatment and after 3 cycles of chemotherapy. After three cycles of therapy, 20 (19.6%) patients had progressive disease (PD), 41 (40.1%) had stable disease (SD), and 41 (40.1%) demonstrated a partial response (PR). In 62 (60.7%) treatment was with capesitabin plus XELOX therapy, and in 40 (39.2%) it was XELOX-Bevacizumab combination therapy. There was no difference among three groups before the treatment in terms of MCV, MPV, PCT, PLT, and NLR. MCV showed significant increase in chemotherapy response groups (PR and SD). In addition, a significant decrease was observed for platelet count in chemotherapy response groups. While NLR decrease was seen in only a PR group, PCT decrease was observed in all three groups. PCT and PLT values were higher in patients receiving Bevacizumab. PLT, PCT, MPV, and NLR values were decreased due to Capecitabine- based chemotherapy, however MCV was increased. PCT and PLT values were higher in patients who received Bevacizumab than those who did not. MCV, PLT, and NLR can be considered as important factors in predicting response to colorectal carcinoma treatment.

Abstract P4-14-04: AVANTI: A non-interventional study examining the combination of bevacizumab with paclitaxel or capecitabine in metastatic breast cancer

Abstract Background: We initiated a large, multicentre, non-interventional study (NIS) to determine the safety and efficacy of treatment, as well as the selection criteria that influence choice of therapy (bevacizumab plus paclitaxel or capecitabine), for patients with metastatic breast cancer (MBC) treated in the context of routine oncology practice in Germany. The study also aimed to gather information on patient-reported quality of life and treatment satisfaction. Here we present an interim analysis of the safety and efficacy data. Methods: Pre- or postmenopausal female patients aged ≥18 years with previously untreated locally advanced, recurrent, or MBC were enrolled if they were considered eligible for treatment with a combination of bevacizumab and either paclitaxel or capecitabine. Endocrine pretreatment was allowed. Patients with contraindications to bevacizumab were excluded. Kaplan-Meier estimates and Cox-regression were used to model survival data. Results: Since October 2009, 1,807 patients have been recruited; this analysis includes data for 1,464 patients with a median age of 60.4 years (range: 23.6–86.4). Most patients had a performance status of 1 (43.1%) and HER2-negative (83.5%), hormone receptor-positive (70.2%) disease. The most common sites of metastasis were bone (52.3%), liver (39.3%) and lungs (33.4%); 736 patients (50.3%) had at least two documented metastatic sites. Bevacizumab plus paclitaxel (68.5% of patients) and bevacizumab plus capecitabine (12.0%) were the most frequently prescribed therapies. Other bevacizumab-containing combination regimens were prescribed to the remaining 19.5% of patients. The treatment decision factors cited most often were efficacy of therapy (62.4%), therapy guidelines (49.7%), tolerability of therapy (40.6%) and HER2 status (38.1%). The overall response rate (complete response [CR] + partial response [PR]) was 48.5% with 5.9% of patients achieving a CR. The disease control rate (CR + PR + stable disease) was 72.7%. At the time of data cut-off, 414 patients (28.3%) had experienced a progression-free survival (PFS) event. Median PFS was 9.5 months (95% CI: 8.8–10.1). Adverse events (AEs) and serious AEs were reported in 457 (31.2%) and 109 patients (7.4%), respectively. The most frequently reported AEs were hypertension (6.1% of patients), fatigue (5.5%), sensory neuropathy (4.6%), leukopenia (4.0%), nausea (4.2%) and diarrhoea (3.6%). Treatment was discontinued due to AEs in 72 patients (4.9%). Conclusions: Interim results of this large NIS demonstrate that bevacizumab plus either paclitaxel or capecitabine combination therapy is well tolerated and active in patients with MBC representative of those treated in routine oncology practice. Follow-up is ongoing and final results of this interim analysis, as well as subgroup analyses, will be reported at the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-14-04.

Abstract OT3-1-08: The PROCEED trial KCSG BR11-01: Phase III multicenter randomized open label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer

Abstract Background: Most patients with metastatic breast cancer (MBC) experience disease progression after being treated with an anthracycline or taxane. Irinotecan, a semisynthetic agent derived from the natural alkaloid camptothecin is metabolized to the active metabolite SN-38 which targets topoisomerase I leading to single and double strand DNA breaks. Irinotecan as a single agent demonstrated tumor activity with an objective response rate ranging from 5 to 23% in patients with MBC refractory to taxane and anthracycline. Irinotecan increased the activity of 5-FU, the active metabolite of capecitabine, and overcomes the negative effect of thymidylate synthase overexpression, which is the main target of an active metabolite of 5-FU. A phase II study that evaluated the efficacy and safety of irinotecan and capecitabin combination (IX) showed that the median progression free survival (PFS) was 7.6 months (95% CI, 5.0-10.2months), and the median OS was 22.6 months (95% CI, 15.4 – 29.8 months) with good tolerability in anthracycline and taxane pretreated MBC patients. Based on these results, we planned to conduct a multicenter, randomized phase III study which assesses the efficacy of irinotecan and capecitabine combination therapy compared with capecitabine alone in patients with anthracycline and taxane resistant MBC. Methods: In this trial, patients with HER2 normal tumor who previously received anthracycline and taxane based chemotherapies are enrolled. Eligible patients are randomly assigned in a 1:1 ratio to receive irinotecan plus capecitabine or capecitabine alone. The primary end point of this trial is PFS and a total number of accrual patients will be 222. Randomization is done using a random block size permutation method and stratified by hormone receptor status (negative vs. positive), first line vs. ≥second lines, visceral metastasis (negative vs. positive). Patients receive irinotecan at 80 mg/m2 on day 1 and 8 every 3 weeks and capecitabine 1000mg/m2 bid from day 1 to day 14 every 3 weeks. In control arm, patients receive capecitabine 1250mg/m2 bid from day 1 to day 14 every 3 weeks. Response will be assessed using RECIST1.1 criteria and toxicity will be graded according to NCI-CTCAE 4.0 criteria. Study Status: A total of 107 patients consented for the study since June 2011, and accrual is ongoing. Clinical trial information: NCT01501669. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-08.

Lapatinib plus capecitabine for HER2-positive advanced breast cancer: a multicentre study of Anatolian Society of Medical Oncology (ASMO)

Lapatinib is the first dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2/neu) and epidermal growth factor receptor (EGFR). The present study evaluated the efficacy and tolerability of the combination of lapatinib and capecitabine in patients with metastatic breast cancer (MBC) who progressed after therapy with trastuzumab, a taxane and/or anthracycline. A total of 203 patients with a median age of 48 years (range: 25–82 years) were evaluated retrospectively in 11 centres between September 2007 and May 2011. All the patients had HER2-positive MBC progressing after trastuzumab and chemotherapy including an anthracycline and/or taxane. All patients were treated with the combination of lapatinib (1250 mg/day, continuously) and capecitabine (2000 mg/m2 on days 1 through 14 of a 21-day cycle). Data on demographics, clinical outcome, and toxicity were collected for descriptive analyses. The median follow-up was 10·7 months (range: 1–40 months). An overall response rate (ORR) of 33·4% was achieved including 7 complete responses (CR, 3·4%), 61 partial responses (PR, 30·0%), and 44 stable disease (37·9%). Clinical benefit rate of 71·3% was achieved. Median progression-free survival (PFS) was 7 months (95% CI: 6–10 months), with a median overall survival (OS) of 15 months (95% CI: 12–18 months). The most common side effects were hand–foot syndrome (46·8%), nausea (42·3%), fatigue (42·2%), anorexia (38·5%), diarrhea (31·5%), and rash (29·6%). Grade 3–4 toxicities were identified as hand foot syndrome (7·9%), diarrhea (6·9%), fatigue (5·9%), and rash (5·4%). There were no symptomatic cardiac events. Lapatinib and capecitabine combination therapy is effective and well tolerated in patients with MBC who had progressive disease after trastuzumab, taxane, and/or anthracycline therapy, as evidenced by this retrospective evaluation. Toxicity was mild to moderate with low grade 3–4 toxicity.

A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer

BackgroundThe safety and efficacy of neratinib monotherapy were compared with that of lapatinib plus capecitabine in patients with human epidermal growth factor receptor-2-positive (HER2+), locally advanced/metastatic breast cancer and prior trastuzumab treatment. MethodsPatients received neratinib 240mg/d continuously (n=117) or lapatinib 1250mg/d continuously plus capecitabine 2000mg/m2 per day on days 1–14 of each 21-d cycle (n=116). The primary aim was to demonstrate non-inferiority of neratinib for progression-free survival (PFS). FindingsThe non-inferiority of neratinib was not demonstrated when compared with lapatinib plus capecitabine (hazard ratio, 1.19; 95% confidence interval, 0.89–1.60; non-inferiority margin, 1.15). Median PFS for neratinib was 4.5months versus 6.8months for lapatinib plus capecitabine and median overall survival was 19.7months versus 23.6months. Objective response rate (neratinib, 29% versus lapatinib plus capecitabine, 41%; P=0.067) and clinical benefit rate (44% versus 64%; P=0.003) were lower for the neratinib arm but consistent with previously reported results. In both treatment arms, diarrhoea was the most frequently reported treatment-related adverse event of any grade (neratinib, 85% versus lapatinib plus capecitabine, 68%; P=0.002) and of grade 3/4 (28% versus 10%; P<0.001), but was typically managed with concomitant anti-diarrhoeal medication and/or study treatment modification. Importantly, neratinib had no significant skin toxicity. InterpretationThe results are considered as inconclusive since neither inferiority nor non-inferiority of treatment with neratinib versus lapatinib plus capecitabine could be demonstrated. The study confirmed relevant single-agent clinical activity and acceptable overall tolerability of neratinib in patients with recurrent HER2+ advanced breast cancer.

Phase II study of weekly scheduled irinotecan and capecitabine treatment in advanced colorectal cancer patients.

e14644 Background: The clinical application of combination therapy of irinotecan and capecitabine is at a standstill due to the consideration on severe diarrhea. The aim of the current phase II study was to explore the optimal administration mode of these two drugs, and evaluate the safety and efficacy of weekly-scheduled XELIRI regimen (wXELIRI) in mCRC pts. Methods: Pts with unresectable, histologically confirmed mCRC were enrolled to receive wXELIRI: irinotecan 90mg/m(2) on Day 1 and capecitabine 1200 mg/m(2) bid on Days 1-5 weekly. Both the first-line pts and second-line treatment pts who failed with FOLFOX or XELOX were eligible. The primary endpoint was rate of Grade 3/4 diarrhea. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and other safeties. Results: From January 2011 to May 2012, totally 43 pts with measurable mCRC were enrolled, 18 of them were male and 25 were female. The median age was 60 yrs (range 32-70). No Grade 4 diarrhea was observed and the rate of grade 3 diarrhea was 4.7%. The most common Grade 3/4 toxicities included leucocyte(11.6%), neutrophile (18.6%), vomiting (4.7%), fatigue (2.3%), hand-foot-syndrome (2.3%) . With a median follow-up of 19.0 months, 23 PFS events were observed. The mPFS for all the 43 pts was 6.1 mons and the mOS was 15.5 mons. For the 31 first-line treatment pts, the mPFS was 7.5 mons and the mOS has not reached. In the second-line treatment group (12 pts), the mPFS was 5.4 mons and mOS was 13.8 mons. Conclusions: The weekly-scheduled irinotecan and capecitabine combination has a low rate of severe diarrhea and acceptable toxicity profile. It could be an alternative regimen for mCRC pts, especially in the second-line setting. Clinical trial information: NCT01322152.