Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group

BackgroundThis randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer (mCRC).Patients and methodsPatients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m²/day 1 plus capecitabine 1000 mg/m² bid/days 1–14 or with irinotecan 200 mg/m²/day 1 plus capecitabine 800 mg/m² bid/days 1–14 both every 21 days. The primary end point was 6 months progression-free survival (PFS).ResultsA total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOx–bevacizumab: n = 127; mCapIri–bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%–84%) and 84% (95% CI, 77%–90%). Median PFS and OS were 10.4 months (95% CI, 9.0–12.0) and 24.4 months (95% CI, 19.3–30.7) with CapOx–bevacizumab, and 12.1 months (95% CI, 10.8–13.2) and 25.5 months (95% CI, 21.0–31.0) with mCapIri–bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx–bevacizumab and in 16% with mCapIri–bevacizumab.ConclusionsBoth, CapOx–bevacizumab and mCapIri–bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.     

A Phase II Trial of FOLFOX6 and Cetuximab in the First-line Treatment of Patients With Metastatic Colorectal Cancer

IntroductionThis phase II trial evaluated the efficacy and safety of cetuximab combined with FOLFOX6 (leucovorin [LV] 5-fluorouracil [5-FU]/oxaliplatin) in the first-line treatment of patients with advanced or metastatic colorectal cancer.Patients and MethodsPatients with locally advanced or metastatic CRC who had received no previous therapy for advanced disease were treated with cetuximab at a loading dose of 400 mg/m² followed by 250 mg/m² weekly and a FOLFOX6 regimen every 2 weeks consisting of oxaliplatin 85 mg/m², LV 400 mg/m², and 5-FU bolus 400 mg/m² followed by 5-FU continuous infusion 2400 mg/m² over 46 hours.ResultsA total of 82 eligible patients were enrolled; epidermal growth factor receptor expression was positive in 67 patients. The overall response rate was 44.8%. In addition, 30 patients (44.8%) in the evaluable population experienced stable disease. Median time to progression or death was 9.3 months (95% CI, 7.0-11.3 months), and median survival was 21.7 months (95% CI, 17.5-27.8 months). Patients who experienced skin toxicity had a statistically significant and longer median survival time than those patients with no skin toxicity (P = .0001). The most commonly observed toxicities were neutropenia (65%), fatigue (56.3%), diarrhea (53.8%), nausea (50%), acneiform rash (41.3%), and stomatitis (35%).ConclusionOur results demonstrate that cetuximab can be safely combined with FOLFOX6 for the first-line treatment of patients with metastatic CRC (mCRC). The efficacy parameters are similar to other first-line regimens in mCRC. Because of the emergence of KRAS as a predictive marker, this regimen has promise in KRAS wild-type mCRC.     

Capecitabine versus 5-fluorouracil in colorectal cancer: where are we now?

Fluorouracil (5-FU) remains the most widely used agent for colorectal cancer. Capecitabine is a rationally designed 5-FU pro-drug developed to mimic the continuous infusion of 5-FU while avoiding complications and inconvenience of intravenous administration. Capecitabine is absorbed intact from the gastrointestinal tract, converted enzymatically to active 5-FU, and released directly into the tumor. Capecitabine’s efficacy and safety are shown in multiple phase III trials across different disease stages and therapy lines. Three randomized phase III trials demonstrated the equivalence of capecitabine plus oxaliplatin (XELOX) versus 5-FU/leucovorin (LV)/oxaliplatin (FOLFOX). The safety of capecitabine compared with 5-FU depends on the regimen of 5-FU used. The adverse event rate with oxaliplatin in combination with infusional 5-FU is similar to that of capecitabine plus oxaliplatin but is associated with more neutropenia and venous thrombotic events; capecitabine plus oxaliplatin-based regimens tend to be associated with more grade 3 diarrhea and hand-foot skin reaction. Combination therapy with capecitabine and irinotecan (CapeIRI) versus 5-FU/LV and irinotecan (FOLFIRI) had more variable results; some former schedules resulted in excessive treatment-related toxicity. More recent data show that lower capecitabine and irinotecan doses, different schedules, and combination with targeted agents (e.g, bevacizumab) have resulted in more favorable outcomes.     

Capecitabine combined with oxaliplatin (CapOx) in clinical practice: how significant is peripheral neuropathy?

BackgroundThere is speculation that peripheral neuropathy (PN) with capecitabine and oxaliplatin (CapOx; 130 mg/m², day 1, every 21 days) may be more common than with FOLFOX4 (5-fluorouracil and oxaliplatin 85 mg/m², day 1, every 14 days). We aimed to determine PN incidence and associations during CapOx, and 6 and 12 months after CapOx.Patients and methodsRetrospective audit of 188 oxaliplatin-naive colorectal cancer patients (87 adjuvant, 101 palliative) who received at least one cycle of CapOx. Neurosensory Common Toxicity Criteria Adverse Events version 3 were applied.ResultsOverall, 94% experienced acute PN. Worst severities for adjuvant and palliative patients, respectively, were grade 1, 44% and 54%; grade 2, 35% and 32%; grade 3, 16% and 3%; grade 4, 0% and 1% and grade unclear 1% and 1%. Two patients developed PN after CapOx completion despite no symptoms during treatment. Chronic PN at 6 months affected 57% and 18% of adjuvant and palliative patients, respectively. At 12 months, 35% and 16% were affected. Chronic PN at 12 months was associated with cumulative oxaliplatin dose but not age, gender, acute myotonia, pseudolaryngospasm or grade 2 or more PN during treatment.ConclusionIncidence of acute PN during CapOx appears similar to FOLFOX4 but chronic PN in adjuvant patients may be more common with CapOx.     

Bolus 5-fluorouracil (5-FU) In Combination With Oxaliplatin Is Safe and Well Tolerated in Patients Who Experienced Coronary Vasospasm With Infusional 5-FU or Capecitabine

Introduction

Coronary vasospasm associated with fluoropyrimidine (FP)-based chemotherapy is a potentially serious complication and reported to occur more often with infusional 5-fluorouracil (5-FU) or capecitabine than with bolus 5-FU. Given the additional benefit of oxaliplatin over FP alone in the management of colorectal cancer, retaining oxaliplatin in the treatment regimen is desirable, but the safety of combining bolus 5-FU with oxaliplatin in patients with FP-induced vasospasm is not well established. We performed a retrospective review to explore the safety of substituting FLOX (bolus 5-FU, oxaliplatin, leucovorin) for FOLFOX (infusional 5-FU, oxaliplatin, leucovorin) and CAPOX (capecitabine, oxaliplatin) in patients who had FP-induced coronary vasospasm.

Cetuximab is associated with excessive toxicity when combined with bevacizumab Plus mFOLFOX6 in metastatic colorectal carcinoma

BackgroundThe bevacizumab-cetuximab combination has shown promising activity in chemotherapy-refractory metastatic colorectal cancer (mCRC). We sought to determine the safety and efficacy of cetuximab added to bevacizumab plus standard mFOLFOX6 (modified 5-fluorouracil [5-FU]/leucovorin/oxaliplatin) as first-line therapy for mCRC.Patients and MethodsSixty-six patients received cetuximab (400 mg/m² loading dose, then 250 mg/m² weekly intravenously [I.V.]) plus bevacizumab 5 mg/kg and mFOLFOX6 chemotherapy every 2 weeks. The primary endpoint was toxicity.ResultsThe most common grade 3-4 events included diarrhea (14%), fatigue (14%), neuropathy (12%), venous thrombosis (9%), acneiform rash (8%), and desquamation (8%). A protocol-defined prohibitive adverse event occurred in 4 patients (6%), including 2 treatment-associated deaths. Thirty-seven patients (56%) discontinued therapy before disease progression because of either toxicity (n = 19; 29%) or patient withdrawal (n = 18; 27%). Twenty-eight of 37 patients (76%) who discontinued therapy before disease progression did so because of cetuximab-associated toxicity.ConclusionAlthough the addition of cetuximab to bevacizumab plus mFOLFOX6 was not associated with excessive life-threatening toxicity, many patients discontinued therapy because of cetuximab-associated toxicity. Taken together with the results of recently reported phase III trials, cetuximab should not be used concurrently with bevacizumab and infusional 5-FU, leucovorin, and oxaliplatin chemotherapy for the treatment of mCRC.     

XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer.

PURPOSE: Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil (FU), with little toxicity overlap. The XELOX regimen (capecitabine plus oxaliplatin), established in a previous dose-finding study, should improve on infused oxaliplatin with FU and leucovorin (FOLFOX) regimens. The present studies further characterize efficacy and safety of the XELOX regimen. PATIENTS AND METHODS: The antitumor activity of XELOX was investigated in a colon cancer xenograft model. Patients with MCRC received first-line XELOX in 3-week treatment cycles: intravenous oxaliplatin 130 mg/m(2) (day 1) followed by oral capecitabine 1,000 mg/m(2) twice daily (day 1, evening, to day 15, morning). RESULTS: A preclinical study confirmed that capecitabine has supra-additive activity with oxaliplatin. In the clinical study, 53 of 96 patients (55%) achieved an objective response, and 30 (31%) experienced disease stabilization for >/= 3 months following treatment. After 24 months' minimum follow-up, median time to disease progression (TTP) and median overall survival were 7.7 and 19.5 months, respectively. XELOX safety was predictable and similar to the FOLFOX4 regimen, except that myelosuppression was uncommon with XELOX (grade 3 or 4 neutropenia, 7%). Most adverse events were mild to moderate, the most common being acute sensory neuropathy (85%). Sixty-day, all-cause mortality was 2%. CONCLUSION: XELOX is a highly effective first-line treatment for MCRC. Response rates, TTP, and overall survival are similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Capecitabine has the potential to replace FU/LV in combination with oxaliplatin for MCRC.     

Cetuximab plus XELIRI or XELOX for first-line therapy of metastatic colorectal cancer

Modern chemotherapy combinations for metastatic colorectal cancer (mCRC) comprise infusional 5-fluorouracil (5-FU), leucovorin, and irinotecan or oxaliplatin. The fluoropyrimidine derivative capecitabine is at least as effective as 5-FU plus leucovorin bolus regimens. It displays a favorable toxicity profile and offers the advantages of oral administration. The epidermal growth factor receptor antibody cetuximab induces synergistic antitumor activity when combined with chemotherapy. In pretreated patients, cetuximab can restore the sensitivity to irinotecan and, therefore, has been registered in this setting. Several phase I/II trials have investigated the combination of cetuximab with irinotecan-based or oxaliplatin-based chemotherapy for the first-line treatment of mCRC. These combinations have been proven to be safe and have provided promising efficacy data. A recent phase III trial confirmed improved progression-free survival, response rates, and a particularly significant increase of secondary resection rates for the combination of FOLFIRI (infusional 5-FU/leucovorin/irinotecan) plus cetuximab compared with FOLFIRI alone. In this review, we discuss the background of combining XELIRI (capecitabine/irinotecan) or XELOX (capecit-abine/oxaliplatin) with cetuximab for the first-line treatment of mCRC and present available data of these combined cytotoxic and targeted treatment approaches.     

Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer

Purpose

Adding docetaxel to cisplatin and 5-fluorouracil (5-FU) (DCF) significantly improved clinical efficacy in advanced gastric cancer (AGC). To further improve the efficacy and tolerability, we substituted oxaliplatin for cisplatin and capecitabine for 5-FU in the DCF regimen and performed a phase I study to determine the recommended dose (RD) and dose-limiting toxicity (DLT) of docetaxel, capecitabine and oxaliplatin (DXO) combination in patients with AGC.

Materials and methods

Previously untreated patients with histologically proven metastatic AGC and ECOG performance status 0–2 were enrolled. Docetaxel and oxaliplatin were administered i.v. on day 1. Capecitabine was administered orally bid on days 1–14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first two cycles of treatment.

Results

Twenty-one patients were enrolled: 15 patients in dose-escalation phase and 6 patients in the extension at the RD. Median age was 50 years (range 21–65 years). At dose level 3 (60 mg/m² docetaxel, 1,000 mg/m² capecitabine, 100 mg/m² oxaliplatin), 1 diarrhea (DLT) was found among 6 patients while at dose level 4 (60 mg/m² docetaxel, 800 mg/m² capecitabine, 130 mg/m² oxaliplatin), 2 DLTs (febrile neutropenia and diarrhea) were observed among 3 patients. Therefore, the dose level 3 was determined as RD. DLTs include grade 3 diarrhea and febrile neutropenia. Cumulative (all cycles) grade 3/4 toxicity included neutropenia (75%), leucopenia (50%), febrile neutropenia (25%), diarrhea (17%), and neuropathy (17%). Of 14 patients with measurable lesions, 11 achieved partial response and 3 showed stable disease.

Conclusion

The RD of the DXO regimen in patients with AGC is capecitabine 1,000 mg/m² twice daily on days 1–14, in combination with decetaxel 60 mg/m² (day 1) and oxaliplatin 100 mg/m² (day 1) repeated every 3 weeks. The DXO regimen seems to have promising activity and offers an easy alternative to DCF. The toxicities appear to be still substantial, but manageable.     

Gemcitabine (GEM) plus oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX-4) in patients with advanced gastric cancer

Background and aims: oxaliplatin in combination with folinic acid (FA) and infusional 5-fluorouracil (5-FU) has shown significant anti-tumor activity in gastric cancer patients (FOLFOX). Previous studies have shown that gemcitabine (GEM), a new fluorinated anti-metabolite, enhances the individual anti-tumor activity of either 5-FU or oxaliplatin. We have therefore designed a multi-center phase II trial in order to test a novel GEM + FOLFOX-4 regimen in patients with metastatic gastric cancer. Methods: we enrolled 36 patients, 28 males and 8 females, with an average age of 64.4 years (range 37–78), who received bi-weekly treatment with GEM (1,000 mg/m² on day 1), levo-FA (100 mg/m² on days 1 and 2), a 5-FU (400 mg/m²) bolus injection followed by 22-h continuous infusion (800 mg/m²) on days 1 and 2, and oxaliplatin 85 mg/m² in a 4–6 h intravenous (i.v.) infusion before the second FUFA administration on day 2. Results: the most frequent side effect was grade 1–2 hematological toxicity and late sensorial neurotoxicity. Two patients developed hypersensitivity to oxaliplatin while another developed an aseptic eosinophilic pneumonitis. Two patients refused to continue the treatment after two cycles of chemotherapy and were lost at the follow-up. Among the remaining 34 patients four achieved a complete response, 15 a partial response, 12 had a stable disease and three progressed. Conclusions: these results may grant the rationale to evaluate this multi-drug combination in randomized phase III trials in advanced gastric cancer.     

Advances in the treatment of metastatic colorectal cancer

The overall 5-year survival rate for patients with metastatic colorectal cancer (CRC) is less than 10%. Median survival with 5-fluorouracil (5-FU)/leucovorin (LV) therapy is approximately 12 months. Recent additions to the chemotherapy armamentarium for this disease have begun to prolong median survival times. In trials in which patients are exposed to all three approved chemotherapy agents, oxaliplatin, irinotecan, and 5-FU/LV, or capecitabine during the course of their disease, median survival has reached 20 months. The addition of oxaliplatin and irinotecan to 5-FU/LV regimens has also led to the maintenance of quality of life for longer intervals than were traditionally observed with 5-FU/LV alone. Current standard first-line regimens for metastatic CRC are FOLFOX (infusional 5-FU/LV with oxaliplatin) and FOLFIRI (infusional 5-FU/LV with irinotecan). The addition of bevacizumab to a two-drug regimen (irinotecan with 5-FU/LV) prolongs median survival to 20 months, with a modest amount of additional toxicity. Improvements in this median survival have not yet been realized with modifications to the current standard regimens; however, the oral agent capecitabine appears to be a reasonable substitute for infusional 5-FU/LV in combination regimens or as a single agent, with the advantage of reducing the inconvenience of the long infusion time. Ongoing investigations will identify a place for capecitabine, epidermal growth factor inhibitors, and new cytotoxics in the treatment of metastatic CRC.     

Capecitabine plus oxaliplatin for the treatment of colorectal cancer

Based on improved safety and efficacy results, advanced colorectal cancer (CRC) treatment has recently shifted from intravenous bolus 5-fluorouracil (5-FU) monotherapy to standard combinations of prolonged intravenous 5-FU infusion with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). Capecitabine, a rationally designed oral fluoropyrimidine that is converted into 5-FU preferentially at the tumor site, could replace infusional 5-FU as the mainstay of combined chemotherapy treatment for metastatic CRC. Evidently, oral medication obviates the drawbacks of prolonged intravenous infusion. The combination of capecitabine and oxaliplatin is especially attractive owing to its favorable tolerability profile, good activity and convenient administration schedule. Phase III trials comparing capecitabine/oxaliplatin with infusional regimens of 5-FU +/- LV and oxaliplatin in advanced CRC show similar toxicity and efficacy outcomes with both regimens. Capecitabine has the potential to replace 5-FU/LV as the optimal combination partner for oxaliplatin at a higher cost. Capecitabine and oxaliplatin concomitantly with radiation therapy has been evaluated before surgery in rectal cancer treatment. The combination of capecitabine and oxaliplatin, with or without bevacizumab, a monoclonal antibody blocking VEGF, is also being evaluated in early stage colon cancer.     

Commentary on a phase III trial of bevacizumab plus XELOX or FOLFOX4 for first-line treatment of metastatic colorectal cancer: the NO16966 trial

Replacing infusional 5-fluorouracil (5-FU) leucovorin (LV) with oral capecitabine would be more convenient to patients, because it would lead to reduced hospital chair time and infusion-related toxicities. Previous trials with oral capecitabine-based regimens (other than XELOX [capecitabine/oxaliplatin]) have failed to demonstrate the equivalent efficacy of capecitabine based regimens to various 5-FU/oxaliplatin regimens (nonstandard FOLFOX [5-FU/LV/oxaliplatin] combinations); of note, these trials did not use the XELOX and standard FOLFOX regimens. An international phase III trial (NO16966) was initiated to demonstrate the noninferiority of XELOX to FOLFOX4 for the first-line treatment of metastatic colorectal cancer. The protocol was later amended to compare bevacizumab and chemotherapy versus placebo and chemotherapy. The efficacy data showed that XELOX was as effective as FOLFOX4 (progression-free survival [PPS; intent-to-treat population]: hazard ratio [HR], 1.04; 97.5% confidence interval, 0.93-1.16). Also, bevacizumab/chemotherapy(pooled with XELOX or FOLFOX) significantly prolonged PPS (HR 0.83; p=0.0023) compared with placebo and chemotherapy (XELOX/FOLFOX). In subgroup analysis, the addition of bevacizumab to XELOX (9.3 months vs. 7.4 months. HR.0.77; P=0.0026) and FOLFOX4(9.4 months vs. 8.6 months; HR, 0.89; P = 0.1871) prolonged PFS compared with respective placebo arms; however, it did not show statistical significance with the FOLFOX4 regimen. The adverse events were manageable and comparable between treatment arms.     

Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers

Combination protocols of 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan or oxaliplatin have demonstrated high activity in metastatic colorectal cancer. Capecitabine, an oral 5-FU prodrug, may replace infusional 5-FU/LV in combination protocols with irinotecan or oxaliplatin. We therefore initiated a phase II study with capecitabine plus either irinotecan or oxaliplatin to determine the efficacy and toxicity of specific combination protocols in patients with advanced gastrointestinal (GI) tumors. Capecitabine 1000 mg/m(2) taken orally twice a day on days 1-14, plus oxaliplatin 70 mg/m(2) on days 1 and 8, or irinotecan 100 mg/m(2) on days 1 and 8; repeated every 3 weeks in an outpatient setting. Patient and tumor characteristics were as follows: median age, 68 years (range, 34-77 years); sex: 10 women, 33 men; tumor types: 35 colorectal cancer; 8 other GI tumors including 5 gastric, 2 pancreatic, and 1 duodenal cancer. All 43 patients treated were evaluable for toxicity (capecitabine/oxaliplatin, 24 patients; capecitabine/irinotecan, 19 patients), and 39 were evaluable for efficacy (capecitabine/oxaliplatin, 22; capecitabine/irinotecan, 17). Grade 3/4 toxicities (National Cancer Institute Common Toxicity Criteria Version 2.0) were limited to diarrhea, 9 patients (capecitabine/irinotecan, n = 5; capecitabine/oxaliplatin, n = 4); hand-foot syndrome, 1 patient (capecitabine/irinotecan); nausea, 2 patients (capecitabine/oxaliplatin); vomiting, 1 patient (capecitabine/oxaliplatin); and peripheral neuropathy, 1 patient (capecitabine/oxaliplatin). No grade 3/4 myelosuppression was noted for either protocol. Capecitabine/irinotecan and capecitabine/oxaliplatin demonstrated significant clinical activity in colorectal cancer and other GI cancers as first-line and salvage therapy. Capecitabine/oxaliplatin and capecitabine/irinotecan show an excellent safety profile and clinical activity in colorectal cancer and other advanced GI tumors. The main toxicity in both arms was manageable diarrhea. This trial served as basis for a randomized multicenter phase II study comparing capecitabine/oxaliplatin and capecitabine/irinotecan as first-line therapy in patients with advanced colorectal cancer.     

A four-arm, randomized, multicenter phase II trial of oxaliplatin combined with varying schedules of 5-fluorouracil as first-line therapy in previously untreated advanced colorectal cancer

BACKGROUND: Oxaliplatin combined with 5-fluorouracil (5-FU), with or without leucovorin (LV), is effective and well tolerated for first-line therapy of advanced colorectal cancer (CRC). However, there is no consensus as to which oxaliplatin/5-FU-containing regimen is superior in the first-line setting. This randomized, multicenter phase II trial was designed to evaluate and compare the efficacy of 4 different oxaliplatin/5-FU regimens. PATIENTS AND METHODS: Patients with previously untreated metastatic CRC (mCRC; n = 129) were randomized to 1 of 4 treatment regimens: (1) continuous 5-FU infusion plus oxaliplatin (n = 23); (2) weekly 5-FU bolus with LV plus oxaliplatin (n = 40); (3) oxaliplatin with 2-day infusion 5-FU/LV (FOLFOX4, n = 41); and (4) chronomodulated 5-FU plus oxaliplatin (n = 25). RESULTS: Overall response rates, after expert assessment, ranged from 24% to 34%, and median progression-free survival (PFS) ranged from 6 months to 8 months. Although no significant differences in efficacy were detected in pairwise comparisons of the 4 different regimens, patients randomized to FOLFOX4 had the highest response rate and longest PFS. The FOLFOX4 regimen was also associated with the lowest incidence of severe (grade 3/4) toxicity, with the exception of cumulative peripheral neurotoxicity. CONCLUSION: This randomized phase II trial provides evidence that oxaliplatin/5-FU regimens are effective and well tolerated for first-line therapy of previously untreated mCRC. The FOLFOX regimens are now an established standard for CRC.     

Phase I study of biweekly oxaliplatin,gemcitabine and capecitabine in patients with advanced upper gastrointestinal malignancies

BackgroundOxaliplatin, gemcitabine and capecitabine are all active agents against upper gastrointestinal and pancreaticobiliary cancers.Patients and methodsPatients with upper gastrointestinal malignancies treated with 0–2 prior chemotherapy regimens received oxaliplatin (85–100 mg/m²) as a 2-h i.v. infusion with gemcitabine (800–1000 mg/m²) at a constant rate i.v. infusion (CI) of 10 mg/m²/min on days 1 and 15 of a 28-day cycle. Capecitabine (600–800 mg/m²) was administered orally twice a day on days 1–7 and 15–21. A three per cohort dose escalation schema was used to determine the maximum tolerated dose (MTD) and the dose-limiting toxic effects (DLTs) of this combination regimen.ResultsThirty patients with advanced upper gastrointestinal malignancies were enrolled. The MTD was defined as oxaliplatin 100 mg/m² i.v. over 2 h plus gemcitabine 800 mg/m² i.v. at a CI of 10 mg/m²/min on days 1 and 15 with capecitabine 800 mg/m² p.o. b.i.d. days 1–7 and 15–21 of a 29-day cycle. DLTs include grade 3 fatigue and grade 3 dyspnea. One complete and two partial responses were observed.ConclusionsThis biweekly schedule of oxaliplatin, gemcitabine and capecitabine is tolerable and warrants further investigation in biliary and pancreatic malignancies.     

Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.     

Oxaliplatin plus oral fluoropyrimidines in colorectal cancer

The medical treatment of colorectal cancer (CRC) has rapidly evolved in recent years with the introduction of novel cytotoxic drugs into clinical practice such as irinotecan, oxaliplatin, and capecitabine. Combination regimens using infusional 5-fluorouracil (5-FU)/leucovorin (LV) plus either oxaliplatin or irinotecan have demonstrated clinically meaningful, high efficacy in advanced CRC. Based on the results of the Intergroup trial N9741, FOLFOX4, a combination of infusional plus bolus 5-FU/LV and oxaliplatin, has emerged as the standard first-line therapy in the palliative setting. However, infusional 5-FU-based regimens carry the need for use of central venous lines and implantable ports to allow treatment on an outpatient basis and are thus inconvenient and expensive. The use of oral fluoropyrimidines (capecitabine or uracil/tegafur [UFT] plus LV) as substitutes for infusional 5-FU in combination protocols with oxaliplatin offers greater convenience, at the same time conceivably maintaining the high efficacy and tolerability observed with intravenous protocols. Various phase I/II trials have recently been reported that investigated oxaliplatin in combination with either capecitabine or UFT/LV in patients with advanced CRC. This review will detail the results of these trials focused on capecitabine-based combinations.     

A multicenter,randomized, open-label study to assess the steady-state pharmacokinetics of bevacizumab given with either XELOX or FOLFOX-4 in patients with metastatic colorectal cancer

Purpose  

To compare the pharmacokinetics (PK) of bevacizumab (BV) at steady-state under two different dosing regimens, 7.5 mg/kg q3w and 5.0 mg/kg q2w, concomitantly with a combination of capecitabine and oxaliplatin (XELOX) and FOLFOX-4 (oxaliplatin in combination with infusional 5-FU/LV), respectively, in patients with metastatic colorectal cancer (mCRC).     

Postoperative chemoradiotherapy in gastric cancer: a phase I study of radiotherapy with dose escalation of oxaliplatin, 5-fluorouracil,and leucovorin (FOLFOX regimen)

Concurrent chemoradiotherapy begins to be more and more widely accepted as a standard adjuvant treatment in gastric cancer. And oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) also reveals to be a very effective regimen in gastric cancer. But the safety and the dosages of FOLFOX combining with radiotherapy are still unknown. This study was to determine the maximum-tolerated dose and the dose-limiting toxicity of FOLFOX with higher-dose concurrent radiotherapy (RT) as adjuvant treatment in patients with gastric cancer. Patients with Stage II/III gastric cancer after surgery were recruited. They received one cycle of induction chemotherapy (standard FOLFOX4). Then, they received 50.4 Gy in 1.8-Gy fractions in combination with two cycles of concurrent FOLFOX, and oxaliplatin among this regimen was administered with escalating doses. Dose-limiting toxicity including grade 3 or grade 4 hematologic and nonhematologic toxicities was investigated. Fifteen patients were enrolled at the following dose levels: oxaliplatin 55 mg/m² (3 patients), 65 mg/m² (6 patients), and 75 mg/m² (6 patients). Dose-limiting toxicity was observed in 1 patient at 65 mg/m² (grade 4 leukopenia) and in 3 patients at 75 mg/m² (1 patient had grade 4 leukopenia, 1 had grade 3 thrombocytopenia, and 1 had grade 3 stomatitis). Combination chemotherapy FOLFOX with oxaliplatin 65 mg/m², d 1; leucovorin 200 mg/m², 2 h, d1–2; 5-fluorouracil 400 mg/m², iv, d 1–2 and 600 mg/m² civ, 22 h, d 1–2 given concurrently with RT (50.4 Gy) can be recommended as a safer and preferable regimen for the adjuvant treatment of patients with gastric cancer.