High-dose Leucovorin Research Articles

Comparison of two doses of leucovorin in severe low-dose methotrexate toxicity – a randomized controlled trial

BackgroundLeucovorin (folinic acid) is a commonly used antidote for severe toxicity with low-dose methotrexate, but its optimum dose is unclear, varying from 15 to 25 mg every 6-h.MethodsOpen-label RCT included patients with severe low-dose (≤ 50 mg/week) methotrexate toxicity defined as WBC ≤ 2 × 10^9/L or platelet ≤ 50 × 10^9/L and randomized them to receive either usual (15 mg) or high-dose (25 mg) intravenous leucovorin given every 6-h. Primary outcome was mortality at 30-days and secondary outcomes were hematological recovery and mucositis recovery. Trial Registration number: CTRI/2019/09/021152.ResultsThirty-eight patients were included, most with underlying RA who had inadvertently overdosed MTX (taken daily instead of weekly). At randomization, the median white blood and platelet count were 0.8 × 10^9/L and 23.5 × 10^9/L. 19 patients each were randomized to receive either usual or high-dose leucovorin. Number (%) of deaths over 30-days was 8 (42) and 9 (47) in usual and high-dose leucovorin groups (Odds ratio 1.2, 95% CI 0.3 to 4.5, p = 0.74). On Kaplan–Meier, there was no significant difference in survival between the groups (hazard ratio 1.1, 95% CI 0.4 to 2.9, p = 0.84). On multivariable cox-regression, serum albumin was the only predictor of survival (hazard ratio 0.3, 95% CI 0.1 to 0.9, p = 0.02). There was no significant difference in hematological or mucositis recovery between the two groups.ConclusionThere was no significant difference in survival or time-to hematological recovery between the two doses of leucovorin. Severe low-dose methotrexate toxicity carried a significant mortality.

Abstract 3741: Folic acid combined chemotherapy has an immediate effect on C1 methionine cycle and consequential DNA methylation in liquid biopsy samples of colorectal cancer patients

Abstract The main function of the single-carbon metabolic cycle is maintaining nucleotide pool and DNA methylation which is highly influenced by the chemotherapy protocols. This study aimed to evaluate the ultrashort effect of reduced folate combined anticancer treatment on peripheral blood parameters of colorectal cancer (CRC) patients. Post-operative CRC patients were treated with chemotherapy using the combination of oxaliplatin, 5-FU, leucovorin, and capecitabine. Blood samples were taken until the beginning of the treatment and immediately after the therapy. Plasma fractions were separated and the levels of S-adenosylmethionine (SAM), S-adenosyl homocysteine (SAH) and the simultaneous quantification of nucleotides (adenine, cytosine, thymine, guanine and uracil) were detected by HPLC-MS/MS. Homocysteine (HCY) was also determined from plasma specimens. Cell-free DNA (cfDNA) was isolated from plasma and DNA methylation was analyzed by LINE-1 bisulfite pyrosequencing. Moreover, LINE-1 methylation statuses were also examined from PBMC cells that were separated from whole blood by a density gradient centrifugation. In each patient, the HCY level of plasma was decreased by an average of 17% after oxaliplatin treatment with the combination of capecitabine (XELOX) and also with 5-FU + leucovorin (FOLFOX) agents. Our study also confirmed that cancer patients have an elevated cfDNA level (avg. 20ng/plasma mL); however, its concentration decreased significantly (p=0.02) on average by 50% after treatment compared to the baseline. The same tendency was observed in the case of SAM after XELOX and FOLFOX adjuvant therapy in plasma samples (p=0.03). Moreover, mostly elevated SAM/SAH ratios were observed in parallel with reduced SAH level after the therapy. Significant (p=0.0001) mean LINE-1 hypomethylation was detected in PBMC (81.84%) compared to cfDNA of plasma (73.76%), furthermore, slightly DNA hypermethylation was noticed in CpG1 position of LINE-1 after chemotherapy in both mononuclear cells and circulating DNA. Lower level of plasma nucleotides was identified in case of adenine, cytosine and uracil after treatment, while thymine and guanine were below the detection limit. The present study demonstrates that the DNA-damaging chemotherapy results in a detectable decrease in cfDNA immediately after the treatment, that was supported by the decrease in the level of the nucleotides measured in the plasma fraction. The methionine cycle is responsible for the DNA methylation maintenance, and though the amount of members of this pathway was reduced, only a moderately increased DNA methylation could be detected even in such a short period time. Co-administration of high dose leucovorin as a folate derivative and a methyl donor with further chemotherapeutic agents may actively contribute to genome alterations. Citation Format: Zsófia Brigitta Nagy, Barbara Kinga Barták, Tamás Fodor, Gellért Balázs Karvaly, Sára Zsigrai, Krisztina Andrea Szigeti, Alexandra Kalmár, Magdolna Dank, István Takács, Béla Molnár. Folic acid combined chemotherapy has an immediate effect on C1 methionine cycle and consequential DNA methylation in liquid biopsy samples of colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3741.

Early, empiric high-dose leucovorin rescue in lymphoma patients treated with sequential doses of high-dose methotrexate.

In patients exposed to high-dose methotrexate (HDMTX; >1g/m2) with a history of elevated methotrexate (MTX) concentrations during previous doses, it is unclear whether prescribing high-dose leucovorin (HDLV) rescue limits future high levels or reduces the likelihood of acute kidney injury (AKI). This retrospective, single-center study longitudinally followed adult lymphoma patients treated with HDMTX between 1/1/2011 and 10/31/2017 from diagnosis until 30 days after the last HDMTX dose. Endpoints included elevated MTX concentrations at 48 h (>1.0 μmol/L) and incident AKI after each HDMTX dose. The 321 included patients had a median (IQR) age of 65 (57, 72) years, 190 (59%) were male, and 293 (91%) were Caucasian. There were 1558 HDMTX doses [median (IQR) 3 (2, 6) doses per patient] prescribed with 265 (83%) patients receiving more than one MTX dose. Those receiving HDLV rescue were more likely to have an elevated MTX concentration after that dose (OR = 2.69, 95% CI: 1.75-4.11, p < 0.001). Receiving HDLV rescue was associated with a greater likelihood of AKI after MTX (OR = 2.18, 95% CI: 1.38-3.43, p < 0.001). Hospital LOS was longer in those prescribed empiric HDLV rescue after MTX than those prescribed standard leucovorin with an estimated difference of 1.1 days, (95% CI: 0.5-1.7, p < 0.001). Sequential HDMTX doses are associated with a significant incidence of elevated MTX levels and AKI during lymphoma management. HDLV rescue prescribed during subsequent MTX doses in patients with a previously elevated level was not associated with improved safety outcomes. The optimal supportive care strategy following HDMTX administration requires further investigation.

Application of blood purification in acute lymphoblastic leukemia pediatric patients with hypermethotrexemia accompanied with acute kidney injury

Objective To investigate the efficacy of blood purification for acute lymphoblastic leukemia pediatric patients with high-dose methotrexate(MTX)-induced hypermethotrexemia and acute kidney injury (AKI). Methods The clinical data of 50 acute lymphoblastic leukemia pediatric patients with hypermethotrexemia (the 45th hour MTX blood concentration >20 μmol/L) and AKI who were admitted to Beijing Children's Hospital Capital Medical University from May 2010 to August 2018 were collected. After the treatment of blood purification, the declining rate of MTX concentration, the incidence of drug-related side effects and the clinical transition were analyzed retrospectively. Results The median MTX blood concentration at the 45th hour after high-dose MTX chemotherapy was 31.5 μmol/L (20.0-80.3 μmol/L). After blood purification treatment, 48 patients (96%) survived, 1 patient (2%) died, and 1 patient (2%) gave up treatment. It costed 10.0 days (7.0-15.0 days) to decline the MTX concentration to the normal level by using blood purification. The median time of purification was 32.5 hours (2.0-168.0 hours), and the days of dialysis were 3.0 days (1.0-9.0 days). The AKI occurred in approximately 96% (48/50) of patients, which was the main side effect. The time of declining the high MTX concentration to the normal was positively correlated with the increase times of serum creatinine (r = 0.371, P = 0.009) and urea nitrogen (r = 0.486, P = 0.001), and the value of the alanine aminotransferase (r = 0.364, P = 0.010) and gamma glutamyl transpeptidase (r = 0.344, P = 0.010), and the days of dialysis (r = 0.532, P < 0.01), but there was no relationship with the 45th hour MTX blood concentration (r=0.110, P = 0.248). The reduction of MTX blood concentration from the 45th hour to the 69th hour after high-dose MTX chemotherapy was negatively correlated with the increase times of urea nitrogen (r = -0.336, P = 0.009) and serum creatinine (r = -0.260, P = 0.035). Conclusion When the MTX blood concentration of patients with hypermethotrexemia and AKI couldn't be declined to the normal level by using high-dose leucovorin, hydration and alkalization, and without the effective detoxification drug (carboxypeptidase G2), they should be offered blood purification, especially continuous renal replacement therapy as soon as possible, which can reduce the blood concentration of MTX quickly and decrease the incidence of side effects effectively. Key words: Leukemia, lymphoblastic, acute; Methotrexate; Blood purification

Efficacy and safety of high-dose vs low-dose leucovorin in patients with colorectal cancer: systematic review and meta-analysis.

The clinical benefits of a combination of leucovorin and fluorouracil have been established in the treatment of colorectal cancer. Due to a leucovorin shortage in 2008, many institutions revised their protocols to reduce the dose of leucovorin. After the shortage was resolved, some hospitals still maintained their modified protocols. Thus, we conducted a systematic review to evaluate the efficacy and safety of low- vs high-dose leucovorin in the treatment of colorectal cancer. The PubMed, Embase and Cochrane databases were searched for studies published before May 2019. The meta-analysis was performed to estimate the pooled effect sizes by using a random effect model. The primary outcomes were median survival time and tumour response rate. Secondary outcomes were haematological and nonhaematological toxicities. Eight randomized controlled trials and four retrospective studies were reviewed. The pooled median survival time was similar between the two dose levels (standard mean difference -0.06, 95% CI -0.19 to 0.08). The pooled tumour response rate was comparatively higher in the high-dose leucovorin regimen (OR0.81; 95% CI 0.55-1.18). No statistically significant difference was found between the haematological and nonhaematological toxicities of the two groups. However, there were fewer diarrhoea events in the low-dose leucovorin regimen. Low-dose leucovorin regimens seemed feasible approaches for colorectal cancer treatment when the shortage happened, because both regimens manifested comparable outcomes in survival time and tumour response rate.

Management of Patients with Acute Methotrexate Nephrotoxicity with High-Dose Leucovorin.

Acute kidney injury complicating high-dose methotrexate (HDMTX) therapy increases the risk for severe mucositis, myelosuppression, and death. It is unclear whether high-dose leucovorin and supportive therapy without the use of glucarpidase can reduce toxicity from HDMTX. The charts of all patients at Memorial Sloan Kettering Cancer Center whose methotrexate (MTX) drug levels at 48 or 72 hours after administration were 10 times or more the toxic level were reviewed between January 2000 and December 2011. Eighty-eight patients (median age 51 years, range 9-90 years) who received 100 courses of HDMTX were identified. Serum creatinine increased by 2-fold from baseline (median, range 1- to 10-fold), but all patients recovered kidney function. Serum levels of MTX were 69 μmol/L (median, range 2.2-400), 6.9 μmol/L (1.3-64), and 2.0 μmol/L (0.05-26) at 24, 48, and 72 hours, respectively, after administration. A statistically significant correlation existed between MTX levels at 48, 72, 96, and 120 hours after administration but not between 24 and 72 hours or subsequent time points. High-dose leucovorin was given in 81% of courses in accordance with institutional protocols in most cases. Myelosuppression was present in 42%; grade III or higher neutropenia in 29%, and thrombocytopenia in 25%. Infectious complications, oral mucositis, and diarrhea occurred in 21%, 17%, and 6% of patients, respectively. Five deaths occurred, none directly attributed to complications from MTX administration. Seven additional patients received glucarpidase at the discretion of a treating physician during the study period, and results are reported separately. Patients who had 100 episodes of HDMTX-associated acute kidney injury were treated with a strategy that only included usual supportive measures and high-dose leucovorin. No deaths were directly attributed to complications related to HDMTX. Glucarpidase, an expensive drug, may not be necessary for a significant number of patients.

Preventing and Managing Toxicities of High-Dose Methotrexate.

High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.

High- versus low-dose leucovorin in the modified FOLFOX6 regimen for first-line treatment of metastatic colorectal cancer.

Background In response to the national leucovorin shortage in 2008, our institution adjusted the modified FOLFOX6 (leucovorin, fluorouracil, and oxaliplatin) protocol to utilize a lower dose of leucovorin (20 mg/m2). This adjustment was based on prospective studies suggesting that lower doses of leucovorin may be equally effective in other fluorouracil containing regimens. This retrospective study evaluates outcomes in metastatic colorectal cancer (mCRC) patients treated with low- (20 mg/m2) vs. high-dose (400 mg/m2) leucovorin in the FOLFOX6 regimen for mCRC. Methods This retrospective analysis included consecutive mCRC patients from 2004 to 2011 if they received at least one cycle of modified FOLFOX6 as first line therapy. Patients who received an initial leucovorin dose other than 20 mg/m2 or 400 mg/m2 on their first cycle were excluded. Patient characteristics included demographics, metastatic site at initial diagnosis, and treatment history including chemotherapy and surgery. Primary outcome was date of death or last contact. Cox proportional hazards regression analysis and Kaplan-Meier survival curves were utilized to evaluate the effect of leucovorin dose on overall survival. Log-rank tests were used to compare median survival times by dose group. Results Of the 93 mCRC patients who received first line modified FOLFOX6, leucovorin 400 mg/m2 was administered to 47 (51%) patients and 20 mg/m2 to 46 (49%) patients. There were no differences of baseline characteristics between the groups with exception of primary site of cancer ( p = 0.038). The overall survival time was 22.5 months (95% CI 16.6-29.6). The median survival time in the leucovorin 400 mg/m2 group was 23.1 months (95% CI 16.2-35.7) compared to leucovorin 20 mg/m2 which was 20.5 months (95% CI 14.2-34.2); p = 0.573. The median survival times in patients with one versus two or more sites with metastasis were statistically different (26.9 vs. 16.2 months, p = 0.009). Metastatic site removal or ablation showed differences in the median survival, 34.2 months (95% CI 20.8-50.9) vs. 16.6 months (95% CI 14.1-23.6) without metastatic disease removal ( p = 0.004). The odds of dying for patients with two metastatic sites was higher compared with the odds of those patients with one site, HR 1.8 (95% CI 1.08-3.0). Patients without metastatic site removal or ablation had higher odds of dying compared to those patients without this procedure, HR 0.47 (95% CI 0.27-0.81). Conclusion In this single center retrospective study, there was no difference in overall survival for mCRC patients treated with first line FOLFOX6 with low- vs. high-dose leucovorin.

Does the dose of leucovorin (LV) matter with 5-fluorouracil (5FU) in colorectal cancer (CRC)?

708 Background: In June 2015 Cancer Care Ontario convened an expert panel to determine if there is an optimum LV dose in 5FU-LV combinations for the treatment of CRC. This request arose out of observed variation in LV dosages between some cancer centers. The research question was effect of LV dose on overall survival (OS), progression free survival (PFS), disease free survival (DFS), response rate (RR) and adverse events/toxicity, given a constant dose of 5FU. Methods: A systematic search was conducted for guidelines (GL) and comparative trials; eligibility included English language, with &gt; 30 patients, that examined different doses of LV where dose of 5FU was not varied. Assessment of studies for inclusion was completed by 4 reviewers. Results: We identified 5 GL, 0 systematic reviews and 12 trials that defined a LV dose in combination with 5FU. None of the GL informed an optimal dose of LV. RR was assessed in 10 trials; 4 showed trends to higher RR with higher LV dose, but differences were not statistically significant (SS) between arms. PFS or DFS was reported in 6 trials and was similar between arms. Time to recurrence reported in one trial that included bevacizumab (BV) was longer in the high dose LV group that was SS. OS was addressed in 10 studies: no difference found in 7 studies; in one RCT OS was longer with the higher dose LV 55 vs. 45 months (p not reported); in one retrospective study OS was 23 vs. 20 months in favor of high dose LV (p not reported); one study of LV and BV had longer OS vs. lower dose LV at 26 vs. 21 months (SS). Toxicity: higher dose LV was associated with greater toxicity in 3 of 4 studies that reported stomatis, and increased rates of diarrhea in 9 of 11 trials. Meta-analysis was not appropriate as studies were too heterogeneous. Conclusions: There is no convincing evidence to identify an optimum dose of LV to be used in 5-FU/LV combinations. Amongst studies that did show a difference the trend was improved survival in favor of the higher dose. Similarly, differences in toxicities when identified were consistently greater with the higher dose LV. The expert panel concludes that the existing literature provides insufficient data to suggest that chemotherapy protocols should deviate from standard protocol doses.

High- versus low-dose leucovorin in the FOLFOX regimen for metastatic colorectal cancer (mCRC).

e14583 Background: In response to the national leucovorin shortage in 2008, our institution adjusted the FOLFOX6 (5-FU, leucovorin, and oxaliplatin) protocol to utilize a lower-dose of leucovorin (20mg/m2). This decision was based on limited prospective studies suggesting lower doses of leucovorin may be equally effective in 5-FU containing regimens. This retrospective study evaluates outcomes in mCRC patients treated with low (20mg/m2) vs. standard high dose (400mg/m2) leucovorin in the FOLFOX regimen for mCRC. Methods: Consecutive patients from 2004 to 2011 treated at Scott & White for mCRC were included if they received at least one cycle of modified FOLFOX6 with or without bevicizumab as first line therapy. Patients that received a leucovorin dose other than 20mg/m2 or 400mg/m2on their first cycle were excluded. Patient characteristics included demographics, site(s) of metastasis at initial diagnosis, and treatment history including chemotherapy and surgery. Primary outcome was date of death or last contact. Univariate and multivariate Cox proportional hazards regression analyses and Kaplan-Meier survival curves compared the effect of leucovorin dose on overall survival. Results: Of the 129 mCRC patients who received first line modified FOLFOX6, leucovorin 400 mg/m2 was administered to 71 (55%) patients and leucovorin 20mg/m2 to 58 (45%) patients. There were no differences between the groups except age at diagnosis, 61 vs. 66 years for high and low dose, respectively (p=0.02). In both univariate and multivariate Cox proportional hazards regression, lack of metastasis to the omentum at diagnosis (P=0.02) and resection or ablation at site of metastasis (P=0.003) were associated with better overall survival. Median survival time was 23 months for high dose group and 20 months for low dose group. There was no statistically significant difference in overall survival between the two groups (HR 1.020, 95%CI 0.677-1.536). Conclusions: In this single center retrospective study there was no difference in overall survival for mCRC patients treated with low (20mg/m2) vs. standard high dose (400mg/m2) leucovorin in first line FOLFOX. Limitations include the retrospective nature of the study and small sample size.

Treatment results and prognostic factors for advanced squamous cell carcinoma of the larynx treated with concurrent chemoradiotherapy

To review our experience with concurrent chemoradiotherapy (CCRT) for patients with advanced resectable squamous cell carcinoma (SCC) of the larynx and to evaluate the factors affecting survival and larynx preservation. Retrospective study. The records of 102 patients with stage III or IV resectable SCC of the larynx treated with CCRT between February 1994 and March 2009 were reviewed. Of 102 patients, 59 were treated with high-dose regimens, including cisplatin, 5-fluorouracil (5-FU), methotrexate, and leucovorin or docetaxel, cisplatin, and 5-FU, and 43 were treated with low-dose regimens, including carboplatin and uracil-tegafur or S-1. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8–2.0 Gray (Gy), to a total dose of 66.0–70.2 Gy. Overall survival (OS), disease-specific survival (DSS), and DSS with larynx preservation were estimated using Kaplan–Meier methods. The log-rank test and Cox proportional hazards regression were used to identify significant prognostic factors for DSS and DSS with larynx preservation. The 5-year OS and DSS for all patients treated with CCRT were 63.9 and 70.7 %, respectively. The 5-year DSS with larynx preservation was 54.1 %. On multivariate analysis, N stage, synchronous multiple primary cancers, and the contents of chemotherapy were significant predictors of OS for patients undergoing CCRT; T stage, N stage, and the contents of chemotherapy were significant prognostic factors for larynx preservation. The treatment method including the indication for CCRT may be determined by the contents of the chemotherapy and the T and N stages of laryngeal SCC. It is important to diagnose multiple synchronous primary cancers before CCRT.

Bimonthly regimen of high-dose leucovorin, infusional 5-fluorouracil, docetaxel, and cisplatin (modified DCF) in advanced gastric adenocarcinoma

The combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) is an effective but highly toxic regimen for the treatment of advanced gastric cancer. To improve tolerability while maintaining the efficacy of the DCF regimen, we developed a modified DCF regimen including an infusional 5-fluorouracil administration according to the de Gramont regimen. In this study, 70 patients with advanced gastric cancer were treated. Each 2-week cycle consisted of docetaxel (60 mg/m(2)), cisplatin (50 mg/m(2)), a 5-fluorouracil (400 mg/m(2)) i.v. bolus, and 5-fluorouracil (2,400 mg/m(2)) i.v. over 46 h plus leucovorin (400 mg/m(2)) i.v. over 2 h. The median progression-free survival and overall survival were 9.0 months (95% CI, 7.1-10.9) and 10.8 months (95% CI, 7.4-14.2), respectively; the 1-year and 2-year overall survival rates were 46.3 and 18.4%, respectively. Twenty-nine (41.4%) partial responses, 19 (27.1%) stable disease, and 22 (31.4%) progression of disease were observed. Grade 3-4 toxicities included neutropenia (37.1%), febrile neutropenia (15.7%), thrombocytopenia (10.0%), anemia (8.6%), nausea and vomiting (10.0%), stomatitis (5.7%), infection (8.6%), and diarrhea (2.9%). Our results show that a de Gramont-based DCF regimen may have tolerable toxicities and be an effective and convenient palliative treatment for advanced gastric cancer.

High and Low Dose Folinic Acid, 5-Fluorouracil Bolus and Continuous Infusion for Poor-Prognosis Patients with Advanced Colorectal Carcinoma

Evaluation and assessment of response rate, duration and toxicity in patients subjected to 5-FU based chemotherapy. The therapeutic ratio shifts with different 5FU/LV regimens and none yet serve as the internationally accepted Gold Standard. A bimonthly regimen of high dose leucovorin is reported to be less toxic and more effective than monthly low dose regimens. We here compare therapeutic responses and survival benefit of the two regimens in poor prognosis patients with advanced colorectal carcinoma. A total of 35 patients with histologically confirmed colorectal carcinoma were subjected to de Gramont and Mayo Clinic regimen. Nineteen patients were treated with high dose folinic acid (200 mg/m2), glucose 5%, 5-FU (400 mg/m2) and 22 hr. CIV (600 mg/m2) for two consecutive days every two weeks. These patients had failed responses to previous chemotherapy and were above sixty years of age with poor general status. Sixteen patients (six below 60 years) with progressive disease were subjected to low dose folinic acid (20 mg/m2)for five days, 5FU(425 mg/m2) injection bolus for 5 days, every five weeks. An initial evaluation was made in sixty days and responders were reevaluated at sixty days interval or earlier in case of clinical impairment. Based on positive prognosis, the therapy was continued. Evaluation of treatment response was made on the basis of WHO criteria. The response rate was 44% in thirty four evaluable patients, with 4 complete responses (11.8%) and 11 (32.4%) partial responses. The two schedules were well tolerated, whereas, mild toxicity without WHO Grade ≥ 2 events was assessed. The response duration was extended (12 months) in a few patients with age above sixty years treated by high dose bimonthly regimen of 5FU/LV. The regimens are safe and effective in advanced colorectal carcinoma patients with poor general status.

Bimonthly Regimen of High-Dose Leucovorin, Infusional 5-Fluorouracil, Epirubicin and Cisplatin (Modified ECF) as Adjuvant Chemotherapy in Resected Gastric Adenocarcinoma

Background: The administration of the de Gramont regimen in combination with cisplatin and epirubicin (modified ECF) has previously been reported as a treatment for advanced gastric cancer, but here we report this regimen combination in an adjuvant setting for the first time. Methods: Forty-eight patients with curatively resected gastric cancer were treated. Each 2-week cycle consisted of epirubicin (50 mg/m²), cisplatin (50 mg/m²), 5-fluorouracil (5-FU) IV bolus (400 mg/m²) and 5-FU IV (2,400 mg/m²) over 46 h plus leucovorin IV (400 mg/m²) over 2 h. Postoperative chemoradiotherapy was also administered to the patients when indicated. We retrospectively reviewed the patients who were treated with modified ECF. Results: The median disease-free survival (DFS) was 40.7 months and the 1-, 3- and 5-year DFS rates were 78.5, 55.7 and 44.6%, respectively. The most common grade 3–4 toxicities were hematological and gastrointestinal. Conclusion: A modified ECF regimen may be an effective and convenient treatment with tolerable toxicities for the adjuvant treatment of gastric cancer. It may provide an alternative regimen to the standard ECF when a continuous ambulatory infusion pump is not feasible or not preferred by the patient.

Clinical study on the effect of the high-dose leucovorin plus fluorouracil in combination with cisplatin in the treatment of advanced esophageal cancer

Objective To observe the effect of high-dose leucovorin(LV)plus 5-fluorouracil(5-Fu)for 48hours infusion in combination with cisplatin(DDP)in treatment of advanced esophageal cancer.Methods Pathological diagnosis of esophageal cancer 60 cases were randomly divided into treatment group of 30 patients,using DDP 25mg/m2 intravenous infusion 30 minutes,d1～3,LV 200mg/m2 intravenous infusion 2 hours,5-Fu 0.5 intravenous injection 10 minutes,and 5-Fu 2.5/m2,continuous infusion with the infusion pump for 48 hours every 21 days,2 cycles of assessment of efficacy.Control group of 30 patients,using DDP 25mg/m2 intravenous infusion 30 minutes,d1～3,LV 60mg/m2 intravenously two hours,d1～5,5-Fu 500mg/m2 intravenously 8 hours every 21 days,2 cycles of assessment of efficacy.Results Short-term effect,treatment group,complete remission(CR)1 patient and partial remission(PR)15 cases,stable(SD)9 cases,progress(PD)5 cases,the total effective rate of CR + PR53.3％(16/30).Control group,PR 11 patients,SD 11 cases,PD 8 cases,no cases of PR,the total effective rate 36.7 ％(11/30).Nausea,vomiting,oral mucositis,bone marrow suppression,diarrhea and hair loss were the main adverse reactions.Two groups are able to withstand,without any Ⅳ toxicities,myelosuppression was significant in control group than the treatment group.Conclusion High-dose LV + 5-Fu 48 hours infusion combined platinum-term efficacy in treatment of advanced esophageal cancer compared with conventional DF program is good,less adverse reactions,should further expand the study. Key words: LV; 5-Fu; DDP; Esophageal cancer,chemotherapy

Postoperative Chemotherapy Followed by Conformal Concomitant Chemoradiotherapy in High-Risk Gastric Cancer

To analyze the efficacy, toxicity, and pattern of relapse after adjuvant cisplatin-based chemotherapy followed by three-dimensional irradiation and concomitant LV5FU2 chemotherapy (high-dose leucovorin and 5-fluorouracil bolus plus continuous infusion) in the treatment of completely resected high-risk gastric cancer. This was a retrospective analysis of 52 patients with high-risk gastric cancer initially treated by total/partial gastrectomy and lymphadenectomy between January 2002 and June 2007. Median age was 54 years (range, 36-75 years). Postoperative treatment consisted of 5-fluorouracil and cisplatin chemotherapy. Adjuvant chemotherapy was followed by three-dimensional conformal radiotherapy in the tumor bed and regional lymph nodes at 4500 cGy/25 fractions in association with concomitant chemotherapy. Concomitant chemotherapy consisted of a 2-h infusion of leucovorin (200 mg/m²) followed by a bolus of 5-fluorouracil (400 mg/m²) and then a 44-h continuous infusion of 5-fluorouracil (2400-3600 mg/m²) given every 14 days, for three cycles (LV5FU2 protocol). Five-year overall and disease-free survival were 50% and 48%, respectively. Distant metastases and peritoneal spread were the most frequent sites of relapse (37% each). After multivariate analysis, only pathologic nodal status was significantly associated with disease-free and overall survival. Acute toxicities were essentially gastrointestinal and hematologic. One myocardial infarction and one pulmonary embolism were also reported. Eighteen patients had a radiotherapy program interruption because of acute toxicity. All patients but 2 have completed radiotherapy. Postoperative cisplatin-based chemotherapy followed by conformal radiotherapy in association with concurrent 5-fluorouracil seemed to be feasible and resulted in successful locoregional control.

6585 POSTER Phase II Study of Low-dose Everolimus Plus Weekly Cisplatin and 24-hour Infusion of High-dose 5-fluorouracil and Leucovorin for First-line Treatment of Metastatic or Recurrent Gastric Cancers

the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin. Results: The hazard ratio for death in the capecitabine group was 0.88 (95% confidence interval [CI], 0.81 to 0.98) in comparison to fluorouracil and the hazard ratio for the oxaliplatin group was 0.93 (95%CI, 0.82 to 1.10) in comparison to cisplatin. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.2 months, 9.3 months, 9.1 months, and 11.5 months, respectively; survival rates at 1 year were 36.6%, 38.9%, 40.1%, and 47.5%, respectively. Overall survival was longer with EOX than with ECF. Toxic effects of capecitabine and fluorouracil were almost similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity but with slightly higher incidences of neuropathy. Conclusions: In our experience, oxaliplatin and capecitabine are more effective than cisplatin and fluorouracil, respectively, in patients with previously untreated esophagogastric cancer.

Phase I, pharmacokinetic, and bone marrow drug-level studies of trimonthly 48-h infusion of high-dose 5-fluorouracil and leucovorin in patients with metastatic colorectal cancers

The primary aim of the high-dose 5-fluorouracil (5-FU) and leucovorin (LV; HDFL48) phase I study was to determine the maximum tolerated dose and dose-limiting toxicity of 5-FU and LV with modified tri-monthly 48-h continuous infusion of high-dose 5-FU/LV in patients with metastatic colorectal cancer. The study also determined the pharmacokinetic parameters of 5-FU, especially steady-state plasma and bone marrow (BM) concentrations. Eligibility included serum triglyceride of more than or equal to 70 mg/dl, adequate BM function, and the major typical trial criteria. Sixteen patients who were enrolled received tri-monthly 5-FU at 2500 mg/m²/48 h/week (with 500 then 250 mg/m²/48 h/week escalation by a conventional 3-3 schema up to 3750 mg/m²/48 h/week) and LV at 300 mg/m²/48 h on days 1, 8, and 15 during a regular 28-day cycle. The maximum tolerated dose of 5-FU was 3750 mg/m²/48 h/week with this tri-monthly schedule. Dose-limiting toxicities were grade III neutropenia with more than 1-week delay of the next cycle, grade III mucositis, diarrhea, and hand-foot syndrome for more than 3 days. The regimen maintains significant concentration differences between steady-state plasma and BM concentrations (8.06 ± 6.39 vs. 2.89 ± 1.01 μmol/l, P=0.021) as measured by high-performance liquid chromatography. Toxicities were of minor grade and were tolerable, with minimal myelotoxicity significantly associated with low steady-state BM concentration. None had 5-FU-related hyperammonemic encephalopathy. Three patients had an objective partial response (18.8%, 95% confidence interval: 4-46%) and two of the 14 patients, who had failed HDFL24 (2600 mg/m²/24 h/week), had a partial response to HDFL48 (14.3% partial response, 95% confidence interval 2-43%). Median progression-free survival and overall survival were 4.1 months (range: 1.8-12.5) and 10.5 months (range: 2.7-32.1), respectively. The efficacy and low myelotoxicity of HDFL48 were attributed to the sustained adequate steady-state plasma concentration and an average 2.63-fold concentration gradient between plasma and BM compartments at steady state. The recommended 5-FU dose for use in future trials was 3500 mg/m²/48 h/week, with a fixed dose of LV at 300 mg/m²/48 h/week.

Phase II study of weekly low-dose everolimus plus weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil and leucovorin for first-line treatment in patients with advanced gastric cancers.

86 Background: Cisplatin-HDFL, consisting of weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil (5-FU) and leucovorin (LV), is an effective and low-toxicity regimen for patients with advanced gastric cancer (GC) in Taiwan (J Clin Oncol. 1994;12(4):875; J Clin Oncol. 2006;24(18S):A14063). Everolimus (RAD001), a derivative of rapamycin, is an orally bioavailable mTOR inhibitor. We have demonstrated that low-dose everolimus (0.5-5.0 nM) sensitizes cytotoxic effects of cisplatin and 5-FU in GC cells (Proc Am Assoc Cancer Res. 2007;48:A4043). Methods: Patients who had pathologically confirmed chemonaive advanced GC, at least 1 measurable lesion, a fasting serum triglyceride level &gt; 70 mg/dl, ECOG PS 0-2, and adequate organ functions were treated with everolimus 10 mg po on days 1, 8, and 15 concurrently with the initiation of chemotherapy; cisplatin 35 mg/m2 iv 24h infusion on days 1 and 8; 5-FU 2,000 mg/m2 and LV 300 mg/m2 (HDFL) iv 24h infusion on days 1, 8, and 15, in a every 28-day cycle. Response assessment was performed every 2 cycles. The primary endpoint was confirmed objective response rate (RR) by RECIST. Results: Between March 2008 and July 2010, 24 patients (M:11, F:13) with a median age of 53 (range: 33-69) were evaluable for response. The overall RR was 50% (95% CI: 29-71%) with 12 partial responders. Among a total of 162 cycles (median: 7, range: 1-13) given, grade (Gr) 3/4 toxicities included neutropenia (4.3%), infection (2.5%), nausea (3.1%) and vomiting (3.1%). Gr 1/2 nausea, vomiting, stomatitis, and diarrhea developed in 19.2%, 15.4%, 14.8%, and 5.5% of cycles, respectively. Skin rash and hand-foot syndrome were mild. One patient developed reversible HDFL-related hyperammonemic encephalopathy. Median progression-free survival was 8.4 months (range: 1.3-15.4+) and median overall survival was 14.8 months (range: 4.0-21.6+). Conclusions: Weekly low-dose everolimus plus weekly cisplatin-HDFL is an effective first-line regimen for patients with advanced GC. Addition of weekly low-dose everolimus to infusional cisplatin-HDFL did not add gastrointestinal toxicities. No significant financial relationships to disclose.

High-Dose Methotrexate-Induced Renal Dysfunction: Is Glucarpidase Necessary for Rescue?

TO THEEDITOR: Widemann et al 1 report the use of glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction. When patients develop delayed excretion of methotrexate and impaired renal function after the administration of high-dose methotrexate there are two equally important imperatives. First, we must protect the patients from the potential toxicity of prolonged exposure to the antifolate drug methotrexate. Potential toxicities include myelosuppression, mucositis, and hepatoxicity, and can be lethal. The second imperative is to have the patient’s renal function return to normal to allow continuation of the chemotherapy needed to treat the underlying malignancy. The authors performed an analysis to determine which factors predicted greater than or equal to grade 4 toxicity. They noted that inappropriate increase in leucovorin predicted perfectly for development of greater than or equal to grade 4 toxicity and therefore could not be included in their multiple factor logistic regression analysis. We have reported our experience treating patients who have delayed methotrexate excretion and renal failure after high-dose methotrexate administration using high-dose leucovorin as the sole form of rescue. 2 All patients in our experience were salvaged. None of our patients died. The authors report that the median time to recovery of renal function for their cohort was 22 days. Our experience, albeit considerably smaller, achieved at least as good a time to recovery of normal renal function. One possible interpretation of the results that the authors report is that glucarpidase was not an essential component of rescue for patients experiencing high-dose methotrexate-related renal dysfunction and that similar results could have been achieved with the use of high-doses of leucovorin alone. Glucarpidase is unquestionably an excellent way to lower the plasma methotrexate concentration. This effect, however, has no impact on intracellular concentrations of methotrexate or on renal function. Protection of cells from intracellular methotrexate still requires the administration of high-doses of leucovorin and renal recovery appears to take place independently of glucarpidase administration. The authors’ conclusion that early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop high-dose methotrexate-related renal dysfunction may be true but the authors should consider the possibility that similar results could be achieved with leucovorin alone.