Oxaliplatin combined with 5-fluorouracil, leucovorin regimen for patients with advanced colorectal cancer

Objective： To observe the efficacy and tolerability of continuously infusing 5-fluorouracil （5-FU） / folic acid combined with oxaliplatin （L-OHP/5-FU/LV regimen） as first line treatment in advanced colorectal cancer. Methods： 23 patients of advanced colorectal cancer were treated with 5-FU 500 mg/d, civ, d 1-d5, d8-d12, leucovorin 100 mg/d, iv gtt, d1, d8, folic acid tablet 60 mg/d, po, d2-d5, d9-d12, and oxaliplatin 65 mg/（m^2·d）, iv gtt, dl, d8, repeated every 21 days （one cycle）. The effect was evaluated after two cycles. Results： Complete response in 2 cases and partial response in 10 cases were observed with an overall response rate of 47.18%. Adverse effects were mainly grade 1-2, including nausea, vomiting, diarrhea, dental ulcer, peripheral neuritis and myelosuppression. Conclusion： L-OHP/5-FU/LV regimen is an effective and better tolerated alternative treatment in advanced colorectal cancer and yields promising clinical application.     

Is salvage chemotherapy for metastatic breast cancer always effective and well tolerated? A phase II randomized trial of vinorelbine versus 5-fluorouracil plus leucovorin versus combination of mitoxantrone, 5-fluorouracil plus leucovorin

Metastatic breast cancer remains an incurable disease and the median overall survival has not significantly improved over the past two decades. Aims of the present randomized phase II trial were to analyse activity and toxicity of chemotherapies with single agent or with combination regimens in previously treated patients with advanced breast cancer. Ninety-nine eligible patients were randomized to receive the following chemotherapies: Arm A – 30mg/m² i.v. weekly; Arm B – leucovorin 100mg/m² i.v. followed by 5-fluorouracil 370mg/m² i.v. days 15, q 28days; Arm C – mitoxantrone 12mg/m² i.v. only day 1+leucovorin 100mg/m² i.v. followed by 5-fluorouracil 370mg/m² i.v. days 13, q 28days. Patients characteristics are comparable in the three groups. The median number of chemotherapy courses administered was 7, 6 and 5 in arm A, B and C, respectively. Objective responses were 24%, 30% and 21% and the median duration of responses were 2, 2.5 and 5.5 months in the arm A, B and C, respectively. Median overall survivals were 9.5, 9 and 9 months in the three arms. No difference was noted comparing the survivals of responding or non responding patients. General toxicity was not mild, with 27.5% of patients experiencing WHO grade 3–4 toxicities.Our results are similar in the three groups of patients and comparable to those reported by other authors. Chemotherapy applied to patients with second or subsequent recurrence allow objective responses in a small percentage of patients. Moreover responders have a negligible prolongation of survival.     

Folate levels measured by LC–MS/MS in patients with colorectal cancer treated with different leucovorin dosages

Purpose

Calcium folinate (leucovorin), which is converted in vivo into biologically active folate, enhances the potency of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer. A common dosage of leucovorin in adjuvant and palliative settings is 60 mg/m². The aim was to determine the levels of tetrahydrofolate (THF), 5,10-methylenetetrahydrofolate (methyleneTHF), and 5-methyltetrahydrofolate (methylTHF) in tumour and mucosa of colorectal cancer patients who received different dosages of leucovorin intravenously at time of surgery.

Methods

Eighty patients scheduled for colorectal resection with indication of colorectal cancer were randomised into four groups to receive leucovorin at 0, 60, 200, or 500 mg/m², respectively. Blood samples were taken 10 and 30 min after leucovorin administration. Biopsy samples from tumour and mucosa were collected and snap-frozen at surgery. The levels of THF, methyleneTHF, and methylTHF in tumour and mucosa were assessed by liquid chromatography electrospray ionisation tandem mass spectrometry (LC–MS/MS) and the results were related to clinical diagnosis and therapeutic regimens.

Results

The folate levels in tissue revealed extensive inter-individual variability. The mean methyleneTHF value for the four treatment groups were 880, 1,769, 3,024 and 3,723 pmol/g_ww. Only half of the patients who received 60 mg/m² leucovorin had higher levels of methyleneTHF in tumour than patients who received 0 mg/m² leucovorin. Rectal cancer patients had significantly lower levels of methyleneTHF compared with colon cancer patients.

Conclusions

There was a large inter-patient variability of tissue folate levels in colorectal cancer patients after supplementation with leucovorin at standardised dosage. High leucovorin doses were needed to exceed baseline methyleneTHF values, especially in rectal cancer patients. The results indicate that the standardised leucovorin dose may be insufficient to attain the full antitumour effect of 5-FU. Further studies are needed to establish whether higher dosage yields a better treatment response.     

A multiple-center phase II study of biweekly oxaliplatin and tegafur–uracil/leucovorin for chemonaive patients with advanced gastric cancer

Purpose  The current study assessed the efficacy and safety of biweekly oxaliplatin combining oral tegafur–uracil/leucovorin in treating chemonaive patients with advanced gastric cancer. Methods  Eligible patients were 18–75 years old, had stage IV disease or post-surgery recurrence, no prior palliative chemotherapy, and an ECOG performance status of 0–2. Patients in the current study received 2-h i.v. infusion of oxaliplatin at a dose of 100 mg/m² after diluting in 500 mL 5% dextrose/water (dexan premedication), and 5-HT3 antagonist biweekly. Oral tegafur–uracil and leucovorin was given at a dose of 300 mg/m²/day and 60 mg/day three times daily from day 1 to 21, respectively, followed by a 1-week rest. Response assessment was based on the RECIST criteria and was performed every two courses. Toxicity was assessed according to NCI common toxicity criteria version 2. Results  From October 2003 to April 2006, 57 patients were evaluated (55 eligible) with a median age of 61 years (range 31–75). According to the assessment of response in 48 evaluable patients, partial response rate was 24/48 (50.0%) (95% CI: 35.23–64.73%) and stable disease was observed in 11 patients (22.92%), and diseased progressed in 13 patients (27.08%). Mean number of oxaliplatin cycles was 3 (0.5–6.5). Median time to progression was 177 days. Median overall survival was 318 days. Major-grade (III/IV) toxicities were diarrhea 25.5%, vomiting 16.5%, anemia 10.9%, numbness 12.7%, thrombocytopenia 7.3%, neutropenia 3.6% and leucopenia 1.8%. Conclusions  Biweekly, oxaliplatin combining oral tegafur–uracil/leucovorin in treating patients with advanced gastric cancer showed acceptable activity and manageable toxicity. This study was presented in part at the 7th International Conference of the Asian Clinical Oncology Society, September 14–28, 2006, Beijing, China.     

Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer – A subgroup analysis of the pivotal NAPOLI-1 trial

ObjectivesPancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial (NCT01494506) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients.Materials and MethodsThis exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis.ResultsOf 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [<65 versus ≥65 years], 0.89/0.88 [<70 versus ≥70 years] and 1.04/0.98 [<75 versus ≥75 years]; P > .25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69% <75 years required a dose delay or reduction due to toxicities (43% versus 32% dose reductions).DiscussionResults suggest that older patients with metastatic pancreatic adenocarcinoma that progressed on prior gemcitabine-based treatment can benefit from second-line therapy, supporting nal-IRI + 5-FU/LV treatment in older patients.     

A phase I/II study of 4′-O-tetrahydropyranyl-doxorubicin, 5-fluorouracil,and high-dose leucovorin as first-line therapy in advanced breast cancer patients

A total of 50 patients were treated weekly with 5-fluorouracil (FU), leucovorin (LV), and 4-O-tetrahydropyranyl-doxorubicin (THP) as first-line chemotherapy for advanced breast cancer (ABC). In phase I the doses of LV (500 mg/m², day 1) and FU (350 mg/m², day 1) were held constant, while the dose of THP (day 1) was escalated, from the initial dose of 10 mg/m² up to the maximum tolerated dose (MTD). Twenty-eight patients entered phase I, and MTD for THP was defined as 35 mg/m² in this combination. Dose-limiting toxicities were myelosuppression and hepatotoxicity. In phase II, another 22 patients were treated with THP at a dose level of 30 mg/m². Including 4 patients already treated at this dose in the first part, 25 patients were evaluable for response: 1 patient obtained a complete response (CR) and 13 showed a partial response (PR), giving an objective response rate of 56%. The median duration of response was 9.1+ months and median survival, 15.5+ months. Side effects were generally mild, with ECOG grade I and II leukopenia in 51% of all cycles and grade III in 3% of the courses. Other toxicity included nausea and vomiting (54% and 8%, respectively) and alopecia (24%), all restricted to ECOG grade I and II. Our results suggest that weekly THP/LV-FU represents an active regimen for first-line treatment of ABC with relative low toxicity.     

Association of adverse events and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil and leucovorin: Is efficacy an impact of toxicity?

BackgroundAdverse events associated with 5-fluorouracil (5FU) based adjuvant therapy in colorectal cancer (CRC) patients may predict survival. We studied whether haematological (leucopenia, neutropenia, thrombocytopenia) or non-haematological (mucositis, diarrhoea, nausea/vomiting, hand-foot syndrome or other toxicity) adverse events were associated with disease-free survival (DFS) or overall survival (OS) in a large patient material treated with 5-fluorouracil based adjuvant chemotherapy.Patients and methodsData from two prospective randomised adjuvant trials were combined to achieve a dataset of 1033 radically operated stage II and III CRC patients treated with either monthly 5FU and leucovorin (LV) as bolus injections (Mayo or modified Mayo) or bi-monthly with bolus and continuous infusion (LV5FU2 or simplified LV5FU2). Toxicities were recorded at each treatment cycle according to NCI-C CTC (the Common Toxicity Criteria of the National Cancer Institute of Canada). The worst toxicity grade was taken into account. The median follow-up time of patients was 6.05 years.Results47% of patients developed neutropenia, 54% nausea/vomiting and 43% mucositis. Any grade neutropenia was associated with improved DFS (hazard ratio (HR) 0.81), any grade nausea/vomiting with improved DFS (HR 0.79) and OS (HR 0.62) and mucositis with improved DFS (HR 0.74) and OS (HR 0.72). Patients experiencing no predefined toxicity had the worst outcome.ConclusionSpecific adverse events related to adjuvant fluorouracil chemotherapy are associated with improved DFS and OS in early stage CRC patients.     

Comparative analysis of the efficacy and safety of chemotherapy with oxaliplatin plus fluorouracil/leucovorin between elderly patients over 65?years and younger patients with advanced gastric cancer

Background

A chemotherapy regimen with oxaliplatin, fluorouracil, and leucovorin is commonly used to treat advanced gastric cancer (AGC). This study was designed to compare the efficacy and the safety of oxaliplatin plus fluorouracil/leucovorin administered biweekly (mFOLFOX6) between elderly patients aged over 65?years and younger counterparts with AGC.

Methods

This analysis included 82 AGC patients (≥65:31, <65:51). Patients with previously untreated chemo-na?ve advanced adenocarcinoma of the stomach received oxaliplatin 85?mg/m², 5-FU bolus 400?mg/m² on day?1 and 5-FU 1,500?mg/m², leucovorin 75?mg/m² 22?h infusion on days?1 and 2 every 2?weeks. The aim of the study was to compare efficacy and safety, including response rate (RR), progression-free survival (PFS), overall survival, and grade ≥3 adverse events, between patients aged ≥65 years and patients aged <65 years.

Results

Median progression-free survival (PFS) was not significantly different between both groups (≥65: 5.8?months, <65: 5.7?months, respectively, HR 0.77, 95% CI: 0.44–1.16, P?=?0.18). Median overall survival was not significantly different between both groups (≥65: 10.3?months, <65: 9.5?months HR 0.83, 95% CI: 0.50–1.37, P?=?0.46). The rate of grade 3 or 4 neutropenia did not differ with age group (≥65: 51.6%, <65: 43.1%); nor did the rates of neutropenic fever (≥65: 16.1%, <65: 5.9%), and infection without neutropenia (≥65: 3.2%, <65: 3.9%). Rates of grade ≥3 toxicities such as thrombocytopenia, nausea/vomiting, or peripheral neuropathy were not significantly different between the two groups.

Conclusions

mFOLFOX6 maintains its efficacy and safety in elderly patients aged over 65?years in comparison with AGC patients aged <65 years. Its judicious use should be considered regardless of age.     

Biochemical modulation of 5-fluorouracil by leucovorin with or without interferon-α-2c in patients with advanced colorectal cancer: final results of a randomised phase III study

5-Fluorouracil (5-FU) remains the mainstay of treatment for advanced colorectal carcinoma, although response rates are generally less than 20%. Improved therapeutic efficacy has been reported using biochemical modulation of 5-FU by leucovorin (LV) or interferon α (IFN), the combination of 5-FU/LV frequently considered as standard therapy in metastatic colorectal cancer. In an attempt to enhance the cytotoxicity of 5-FU, a prospective randomised trial was initiated to compare 5-FU/LV with 5-FU/LV plus IFN. Patients were randomised to receive either LV, 100 mg/m² intravenously (i.v.), followed by 5-FU, 500 mg/m² as a 1-h i.v. infusion, daily for 4 days, followed by weekly infusions until week 8, or the same regimen of 5-FU/LV plus IFN-α-2c, 30 μg subcutaneously (s.c.), three times weekly. Cycles were repeated after a 2-week rest period. Among 269 enrolled patients, 219 were available for response and 243 for toxicity. An objective tumour response was observed in 38 of 107 (36%) and 28 of 112 (25%) patients in the treatment arms with and without IFN, respectively (difference not significant). There was no significant difference between the two groups in response duration (median 8.4 versus 12.1 months), time to treatment failure (median 6.5 versus 4.9 months), or overall survival (median 10.0 versus 12.6 months). However, patients in the IFN arm experienced significantly more haematological and gastrointestinal toxicity and more frequent alopecia. In conclusion, the addition of IFN to 5-FU/LV in the schedules and doses used in the study did not provide any clinical benefit over 5-FU/LV alone and cannot be recommended for routine use in the treatment of advanced colorectal cancer.     

What is the clinical benefit of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer in a pooled analysis of EORTC 22921 and FFCD 9203 trials: Surrogacy in question?

BackgroundTwo phase III trials of neoadjuvant treatment in T3-4 rectal cancer established that adding chemotherapy (CRT) to radiotherapy (RT) improves pathological complete response (pCR) and local control (LC). We combined trials to assess the clinical benefit of CRT on overall (OS) and progression free survival (PFS) and to explore the surrogacy of pCR and LC.Patients and methodsIndividual patient data from European Organisation for Research and Treatment of Cancer (EORTC) 22921 (1011 patients) and FFCD 9203 (756 patients) were pooled. Meta-analysis methodology was used to compare neoadjuvant CRT to RT for OS, PFS LC and distant progression (DP). Weighted linear regression was used to estimate trial-level association (surrogacy R²) between treatment effects on candidate surrogate (pCR, LC, DP) and OS.ResultsThe median follow-up was 5.6 years. Compared to RT (881 pts), CRT (886 pts) did not prolong OS, DP or PFS. The 5-y OS-rate was 66.3% with CRT versus 65.9% in RT (hazard ratios (HR) = 1.04 {0.88–1.21}). CRT significantly improved LC (HR = 0.54, 95% confidence interval (CI): 0.41–0.72). PFS was validated as surrogate for OS with R² = 0.88. Neoadjuvant treatment effects on LC (R² = 0.17) or DP (R² = 0.31) did not predict effects on OS.ConclusionPreoperative CRT does not prolong OS or PFS. pCR or LC do not qualify as surrogate for PFS or OS while PFS is surrogate. Phase III trials should use OS or PFS as primary endpoint.     

Safety analysis of two different regimens of uracil–tegafur plus leucovorin as adjuvant chemotherapy for high-risk stage II and III colon cancer in a phase III trial comparing 6 with 18 months of treatment: JFMC33-0502 trial

Purpose

The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil–tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses.

Methods

Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m²) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated.

Results

A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group.

Conclusions

Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months.