Parallel administration of nanoliposomal irinotecan and levo-leucovorin for pancreatic cancer.

BACKGROUND: Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/levo-leucovorin (Levo-LV) was approved for unresectable pancreatic cancer (UR-PC) in March 2020 in Japan. Levo-LV is administered by intravenous infusion over 120 min following 90 min intravenous infusion of nal-IRI (conventional method), causing a significant burden on both patients and the outpatient chemotherapy room owing to the prolonged administration time. Thus, from July 2021, we introduced the simultaneous intravenous administration of nal-IRI and Levo-LV (parallel method) with the approval of the institutional regimen committee. METHODS: We retrospectively reviewed the data of 69 patients with UR-PC who received nal-IRI plus 5-FU/Levo-LV at our hospital between June 2020 and October 2021. We examined the safety of the parallel method and compared the treatment outcomes and administration times between the two methods. RESULTS: The median age was 66 years (54%, male). Disease statuses were locally advanced, metastatic, and postoperative recurrence after pancreatectomy in 7, 50, and 12 patients, respectively. Nal-IRI plus 5-FU/Levo-LV treatment was second and third-line or later in 35 and 34 patients, respectively. No intravenous line problems were observed during the parallel administration of nal-IRI and Levo-LV. Although there were no significant differences in response rates and adverse events between the two methods, the administration time was significantly shorter in the parallel method than in the conventional method. CONCLUSION: The parallel administration of nal-IRI and Levo-LV is clinically safe and not inferior in efficacy. Moreover, parallel administration may offer convenience to patients and healthcare workers by reducing administration time.

Intravenous route for folate supplementation in a patient with celiac disease treated by pemetrexed-based chemotherapy for non-small-cell lung cancer.

INTRODUCTION: Oral folic acid supplementation is essential for patients treated with pemetrexed, to prevent the risk of severe hematologic toxicity. In case of intestinal absorption disorder, no recommendations exist for intravenous folic acid supplementation. CASE REPORT: We describe a 74-year-old patient with multimetastatic non-small-cell lung adenocarcinoma, receiving first-line chemotherapy with carboplatin AUC5, pemetrexed 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. The patient presented neglected celiac disease, resulting in malabsorption syndrome with iron and folic acid deficiency. The question was how to administer folic acid supplementation during the pemetrexed-based chemotherapy. MANAGEMENT AND OUTCOMES: Intravenous injection of 200 mg levoleucovorin on day 1 of cycle 1 of pemetrexed-based chemotherapy was administered and well tolerated. During the second cycle, the levoleucovorin perfusion was not renewed by omission. The patient was hospitalized for 7 days because of febrile aplasia. Piperacillin-tazobactam was started, and then switched to amoxicillin-clavulanate plus ciprofloxacin. After this episode of post-chemotherapy febrile aplasia, it was decided to systematically supplement the patient with intravenous levoleucovorin, with blood folate concentration monitoring at each cycle. At 16 months after start of treatment, the patient was in complete remission, indicating that the immune-chemotherapy was effective, with no further febrile neutropenia. DISCUSSION/CONCLUSION: This case report highlights intravenous levoleucovorin supplementation as an alternative to oral folic acid if needed during pemetrexed-antifolate-based chemotherapy.

Stability of calcium levofolinate reconstituted in syringes and diluted in NaCl 0.9% and glucose 5% polyolefin/polyamide infusion bags.

PURPOSE: Calcium levofolinate (CaLev) for intravenous administration is commercially available as a powder that must be reconstituted for injection or reconstituted and then diluted before administration. The lack of stability data on CaLev solutions renders necessary extemporaneous manual preparation, preventing the use of automated/semi-automated systems, with a consequent loss in terms of quality and safety. METHODS: The present work assessed the chemical-physical and microbiological stability of CaLev prepared in sodium chloride 0.9%, glucose 5% and water for injections and stored in polyolefin/polyamide bags and polypropylene syringes at 2-8°C protected from light. For this purpose, we developed and validated a new rapid High Performance Liquid Chromatography with Ultra Violet Diode-Array Detection (HPLC-UV-DAD) method. RESULTS: The samples tested were stable for 14 days, retaining >95% of their initial concentration and showing no change in colour, turbidity or pH. Microbiological tests performed on the samples were negative. CONCLUSIONS: Our results confirmed the analytical stability of CaLev in NaCl 0.9%, glucose 5% and water for injection at concentrations used in clinical practice at our institute. This enables our centralized laboratory to organize the preparation of this drug in advance and the use of robots rather than manual preparation reduces the workload and the risk of preparation errors.

Protocol of the EFFORT study: a prospective study of FOLFIRI plus aflibercept as second-line treatment after progression on FOLFOXIRI plus bevacizumab or during maintenance treatment in patients with unresectable/metastatic colorectal cancer.

BACKGROUND: FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. METHODS: EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. DISCUSSION: This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs071190003 . Registered April 18, 2019.

Successful Treatment with 5-fluorouracil and Levofolinate Calcium in Advanced Gastric Cancer Patient with Disseminated Intravascular Coagulation.

A 32-year-old woman was found to have a gastric adenocarcinoma with multiple bone metastases. Chemotherapy in the first, second and third-line was not effective. Blood examinations showed disseminated intravascular coagulation(DIC)at the end of the second-line chemotherapy. The fourth-line chemotherapy, infusional 5-fluorouracil and levofolinate calcium was performed. This resulted in a good response for DIC. This palliative therapy was effective and safety.

Three-Period Bioequivalence Study of Sodium Levofolinate Injection With Calcium Levofolinate for Injection and Sodium Folinate for Injection in Healthy Chinese Subjects.

The aim of this study was to compare the bioequivalence and safety of test preparation sodium levofolinate injection with reference preparations of calcium levofolinate for injection and sodium folinate for injection in China. A single-center, randomized, open-label, 3-period, crossover test was conducted on 24 healthy subjects. Plasma concentration of levofolinate, dextrofolinate, and their metabolites l-5-methyltetrahydrofolate and d-5-methyltetrahydrofolate were quantified by a validated chiral-liquid chromatography-tandem mass spectrometry method. All adverse events (AEs) were documented to evaluate safety as they occurred and evaluated descriptively. Pharmacokinetic parameters (maximum plasma concentration, time to maximum concentration, area under the plasma concentration-time curve over the dosing interval, area under the plasma concentration-time curve from time 0 to infinity, terminal elimination half-life, and terminal rate constant) of 3 preparations were calculated. A total of 8 subjects (10 cases) of AEs occurred in this trial. No serious AEs or unexpected serious adverse reactions were observed. Sodium levofolinate was bioequivalent to calcium levofolinate and sodium folinate in Chinese subjects, and the 3 preparations were all well tolerated.

Levoleucovorin as replacement for leucovorin in cancer treatment.

OBJECTIVE: To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin. DATA SOURCES: A MEDLINE search was conducted for English-language human studies published between January 1980 and April 2012 using the terms l-LV, levoleucovorin, d,l-LV, leucovorin, folinic acid, folinate, 5-formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials. STUDY SELECTION AND DATA EXTRACTION: Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed. DATA SYNTHESIS: From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents. CONCLUSIONS: The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice.

Local recurrence of gastric cancer after total gastrectomy: an unusual presentation.

A 71 years old Italian man had type 3 gastric cancer of the greater curvature. Total gastrectomy with splenectomy and D2 lymph node dissection were performed. After discharge chemotherapy ELF regimen was administered for 6 months. After 16 months from the operation a local recurrence was discovered by CT scan. Surgical en-bloc resection was performed removing pancreatic tail, splenic colic flexure and a portion of left diaphragm. Histological examination confirmed local recurrence of gastric adenocarcinoma infiltrating pancreas, colon and diaphragm with lymph node metastasis.

[A case of colorectal neuroendocrine carcinoma effectively treated with bevacizumab+levofolinate+5-FU chemotherapy].

A 76-year-old woman was admitted to our hospital with diarrhea and weight loss in February 2007. A CT scan revealed a tumor in the abdominal cavity, and although a thorough investigation was conducted, no diagnosis was made. Therefore, she underwent diagnostic surgery in April 2007. Intraoperatively, the tumor was determined to have originated in the transverse colon, with invasion to other organs. The patient underwent a transverse colectomy, partial ileal resection, and partial resection of the bladder and peritoneum were performed. The pathological diagnosis was colorectal neuroendocrine carcinoma. FOLFOX4 chemotherapy was initiated in May 2007. However, a CT scan in June 2007 revealed a recurrent tumor in the right pelvis. Although right hemicolectomy and right oophorectomy were performed in August, a CT scan in September 2007 revealed a recurrent tumor in the right pelvis. Following treatment with bevacizumab+levofolinate+5-FU, the tumor disappeared. The patient continued to receive this chemotherapy regimen until August 2010, and CT scans showed a complete response. Even though colorectal neuroendocrine carcinoma is known to have a poor prognosis, the present case was effectively treated with bevacizumab+levofolinate+5-FU chemotherapy. Herein we provide discussion and suggestions about treatment for colorectal neuroendocrine carcinoma.

Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial.

BACKGROUND: In advanced colorectal cancer, chemotherapy is usually administered without pauses and until progression but patients can experience cumulative toxicity and cannot tolerate a heavy therapeutic charge. AIM: The aim of the present trial was to evaluate whether an intermittent chemotherapy with levo-leucovorin + 5-fluorouracil (5-FU) + irinotecan (CPT-11) was at least as effective as the same regimen given continuously, both administered until progression, in patients affected with advanced colorectal cancer and not previously exposed to chemotherapy for metastatic disease. PATIENTS, MATERIALS AND METHODS: A total of 337 patients from 27 institutions were randomised between levo-leucovorin, 100/mg/m(2) i.v. + 5-FU; 400 mg/m(2) i.v. bolus + 5-FU; 600 mg/m(2) 22-h continuous infusion, days 1 and 2 + CPT-11; 180 mg/m(2) day 1, administered every 2 weeks 2 months on and 2 months off (arm A) and the same regimen administered continuously (arm B), until progression in both arms. The main end point was overall survival (OS), the secondary progression-free survival (PFS) and toxicity. RESULTS: At a median follow-up of 41 months, OS was 18 months in arm A and 17 months in arm B [hazard ratio (HR), 0.88]. Also PFS was comparable in the two groups (6 months in both, with HR, 1.03), and even grades 3-4 toxicity (mainly myelosuppression, fever and diarrhoea) was similar. Second-line oxaliplatin-based treatment was administered in a similar percentage (66%) in the two arms. The median chemotherapy-free period (drug holiday) in arm A was 3.5 months. CONCLUSION: Reducing the charge of therapy in this population did not diminish the efficacy of treatment. Further studies with this strategy, including biologicals, are warranted.

Bowel perforation due to methotrexate therapeutic error: an insidious adverse reaction.

OBJECTIVE: Methotrexate (MTX) is widely used in the treatment of rheumatic and non-rheumatic disorders. Severe adverse effects are often associated with therapeutic errors, such as daily intake rather than weekly intake. Among them, the risk of bowel perforation is extremely rare (0.1%). We describe a case of bowel perforation, occurred following daily intake of MTX. CASE REPORT: A 68-year-old man was prescribed to take MTX 7,5 mg orally once a week, while waiting for switch to abatacept for a recent reactivation of rheumatoid arthritis. After 10 days he started having pharyngodynia, hematochezia and general malaise. At medical examination he presented oral and nasal mucositis; moreover, blood exams showed thrombocytopenia. The anamnesis revealed that he had been taken the prescribed dosage of MTX daily, instead of weekly. Therapy with Lederfolin 1000 mg (mg/m²/die) and urine alkalinization started. After 7 days of hospitalization, there was an abrupt worsening of clinical conditions and an emergency CT scan revealed millimetric gas bubbles indicating bowel perforation. The patient underwent an emergency exploratory laparotomy that resulted in peritoneal toilette and sigma resections. Anatomopathological findings were suggestive of MTX poisoning. CONCLUSIONS: The patient was discharged on the 17th day in good clinical condition.

[Oxaliplatin combined with ELF regimen in the treatment of patients with advanced gastric cancer].

OBJECTIVE: To evaluate the efficacy and safety of the combination of oxaliplatin and ELF (VP16/CF/5-Fu) regimen in the treatment of patients with advanced gastric cancer. METHODS: Oxaliplatin was given at a dose of 100 mg/m(2) i.v. 2 hours D1, calcium folinate (CF) 200 mg/m(2) i.v. 1/2 hour D1 approximately D3, 5-fluorouracil (5-Fu) 500 mg/m(2) i.v. 2 hours D1 approximately D3 and etoposide 100 mg/m(2) i.v. 3 hours D1 approximately D3. Cycles were repeated every 21 days. Efficacy and safety were evaluated every 2 cycles. RESULTS: Sixty-nine patients were enrolled into the study. All cases were pathologically confirmed as gastric cancer (adenocarcinoma in 57 cases and signet ring cell carcinoma in 12 cases). 42 patients had newly diagnosed disease, and 27 patients had received previous chemotherapy. 62 patients were analyzed for response (7 complete responses and 25 partial responses) with total response rate 51.61%. The median time to progression was 5.7 months and the median overall survival was 9.2 months. The most common hematologic toxicities were anemia (29.0%), leucopenia (51.2%) and thrombocytopenia (21.2%). No grade 4 and grade 5 hematologic toxicities were observed. The most common non-hematologic toxicities were nausea (46.5%), vomiting (41.1%), peripheral sensory neuropathy (47.1%), and grade 2 alopecia (27.3%). CONCLUSION: This oxaliplatin combined with ELF regimen shows good efficacy and acceptable safety in advanced gastric cancer patients. It is worthy to be proved as a suitable alternative regimen in this indication.

Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group.

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival.

PURPOSE: To determine tumor response rate, patterns of failure, toxicity, and survival in advanced squamous head and neck cancer after a combined treatment program that consists of induction chemotherapy, organ-sparing surgery, and concurrent chemoradiation. Long-term outcome data are presented. PATIENTS AND METHODS: Between July 1991 and March 1993, 93 patients received three cycles of induction chemotherapy that consisted of cisplatin, fluorouracil (5-FU), l-leucovorin, and alpha-interferon2b (PFLl-alpha) followed by optional limited surgery and six to eight cycles of 5-FU, hydroxyurea, and concurrent radiation (FHX) to a total radiation dose of 65 to 75 Gy. RESULTS: Ninety-three patients were entered onto this study and 97% had stage IV disease, with 66 patients who were N2 or N3. Sixty-one patients (66%) achieved a clinical complete remission (CR) after induction therapy. Thirty-four patients underwent surgery. Seventy-nine patients proceeded to FHX. With a median follow-up time of 43 months for surviving patients, 20 patients have had disease progression (13 local, two distant, five both), and there have been 35 deaths (18 from disease, six treatment-related, two from a second primary, and nine for other medical reasons). At 5 years, progression-free survival is 68%, and overall survival is 62%. Surgery was organ-preserving, as only a single laryngectomy and no glossectomies were performed in primary management. Acute toxicity related to PFLl-alpha consisted of severe or life-threatening mucositis in 57% and leucopenia in 65% of patients. During FHX, 81% of patients had grade 3 or 4 mucositis. CONCLUSION: PFLl-alpha is a highly active regimen that induced clinical CR in two thirds of patients. When followed by limited surgery and FHX, resultant local and distant disease control, organ preservation, and overall 5-year survival are very promising in high-risk stage IV patients. Based on these local control and survival data, further evaluation of this treatment sequence, induction chemotherapy followed by concurrent chemoradiation, is warranted. Identification of similarly active but less toxic regimens is a high priority.

Folinic acid, 5-fluorouracil and etoposide after curative resection for gastric cancer.

BACKGROUND/AIMS: The aim of this study was to evaluate the survival benefit of adjuvant chemotherapy with etoposide, leucovorin and 5-fluorouracil (ELF) in gastric cancer patients undergoing previous surgery with a curative intent. METHODOLOGY: The clinical outcome of 49 patients with resected gastric cancer treated with adjuvant chemotherapy was compared with that of 85 surgically treated historical controls who did not receive any adjuvant treatment. The chemotherapy regimen consisted of six cycles of daily 1-hour intravenous infusions of folinic acid 100 mg/m2 and 5-FU 400 mg/ m2, and a 2-hour infusion of etoposide 100 mg/m2, for three days every 28 days. RESULTS: The 5-year relapse-free survival was 32% in the adjuvant arm and 27% in the control arm (p = 0.6). At the last follow-up, there were 32 deaths in the adjuvant arm and 60 in the control arm. The median duration of survival was respectively 23 and 19 months, and the 5-year survival rates were 34% and 29% (p = 0.4). The chemotherapy was well tolerated. CONCLUSIONS: Our data suggest that ELF adjuvant treatment is a safe and well tolerable combination chemotherapy in patients with resected gastric cancer, but it does not seem to improve prognosis in comparison with historical controls.

A pharmacokinetic and pharmacodynamic investigation of Modufolin® compared to Isovorin® after single dose intravenous administration to patients with colon cancer: a randomized study.

PURPOSE: Leucovorin is commonly used as folate supplement in 5-fluorouracil-based chemotherapy, but needs to be converted to active 5,10-methylenetetrahydrofolate (methyleneTHF) intracellularly. This provides for interindividual differences. MethyleneTHF has recently been developed into the stable, distributable drug, Modufolin®. The aim was to compare the concentration of folate metabolites in tumor, mucosa, and plasma of patients with colon cancer after administration of Modufolin® or Isovorin® (levo-leucovorin). METHODS: Thirty-two patients scheduled for colon resection were randomized to receive Modufolin® or Isovorin® at dosage of 60 or 200 mg/m². The study drug was given as one i.v. bolus injection after anesthesia. Plasma was collected for pharmacokinetic (PK) analysis before, during, and after surgery. Tissue biopsies were collected at surgery. Folate metabolites were analyzed by LC-MS/MS. RESULTS: MethyleneTHF and THF concentrations were significantly higher in mucosa (p < 0.01, both dosages) and tumors (p < 0.01, 200 mg/m²) after Modufolin® as compared to Isovorin® administration. The results correlated with PK observations. The Modufolin® to Isovorin® C(max) ratio for methyleneTHF was 113 at 200 mg/m² and 52 at 60 mg/m²; the AUC(last) ratios were 17 and 9, respectively. The THF plasma concentrations were also higher after Modufolin® administration (C(max) ratio 23, AUC(last) ratio 13 at 200 mg/m²; C(max) ratio 15, AUC(last) ratio 11 at 60 mg/m²). CONCLUSION: Modufolin® administration resulted in significantly higher methyleneTHF levels than Isovorin® and may potentially increase the efficacy of 5-fluorouracil-based chemotherapy. The results encourage further evaluation of Modufolin® as a substitute to Isovorin® including the potential clinical benefits.

Levofolene modulates apoptosis induced by 5-fluorouracil through autophagy inhibition: clinical and occupational implications.

5-Fluorouracil (5-FU), often used in combination with levofolene (LF), can induce, as an important side effect, the hand-foot syndrome (HFS) due to toxicity on keratinocytes. This can also damage workers involved in its handling. In the present study, we investigated the mechanisms of the toxicity induced by 5-FU alone or together with LF on human keratinocytes in culture. We found that the two drugs, as expected, had potentiating activity on keratinocyte growth inhibition and that this effect was mediated by induction of apoptosis. In our experimental model, an increased autophagic vacuole accumulation was observed in keratinocytes treated with 5-FU as a significant increase of the monodansylcadaverine (MDC) labeling (marker of late autophagy vacuoles) was recorded. However, the synergism of 5-FU with LF on apoptotic occurrence was not paralleled by a similar increase in autophagic vacuoles at 72 h suggesting an antagonistic effect of LF on autophagy elicited by 5-FU. Differential effects on reactive oxygen species (ROS) elevation in cells treated with 5-FU alone or the combination between 5-FU and LF were also observed. 5-FU induced a time-dependent increase of both O2- and lipid peroxidation while the combination of 5-FU and LF caused a stronger intracellular O2- increase only at 24 h while at 48 and 72 h its effect was lower when compared with that one of 5-FU alone. On the other hand, the addition of LF to 5-FU caused a stronger increase of lipid peroxidation at 48 and 72 h, but its effects were significantly lower at 24 h. These results suggest for the first time that LF potentiates the cytotoxicity of 5-FU on keratinocytes likely through the antagonism on autophagy escape pathway and consequent apoptosis potentiation.

Treatment of advanced gastric cancer with oral etoposide, leucovorin and tegafur: experience with an oral modification of the etoposide, leucovorin and 5-fluorouracil (ELF) regimen.

Recent data have suggested enhanced therapeutic activity with prolonged administration of both etoposide as well as fluoropyrimidines in the treatment of gastrointestinal malignancies. Based on this rationale, we investigated the clinical effectiveness and tolerance of an oral modification of the widely applied etoposide, leucovorin and 5-fluorouracil (ELF) regimen in patients with advanced gastric cancer. 32 patients with advanced gastric cancer were treated with oral etoposide (100 mg), leucovorin (3 x 100 mg), and tegafur (3 x 200 mg) over 14-21 days for a maximum of six cycles. Objective response was seen in only 5 patients (16%), stable disease was documented in 7 (22%), while the remaining patients progressed during therapy. The median time to progression was 2.8 months (range 0.7-12 months) and median overall survival was 6 months (range 1-18+ months). Due to grade 3 nausea/emesis, 8 patients discontinued treatment prematurely, while 12 patients experienced anorexia and progressive weight loss. Haematological toxicity was modest, with 4 patients developing asymptomatic grade 3-4 granulocytopenia. We conclude that this oral combination regimen cannot be recommended for the treatment of advanced gastric cancer.

New developments in the treatment of gastric carcinoma.

The recent successes being achieved with combination chemotherapy regimens, such as FAMTX (fluorouracil [5-FU], doxorubicin, methotrexate), EAP (etoposide, doxorubicin, cisplatin), and ELF (etoposide, leucovorin, 5-FU), strongly indicate that gastric cancer is chemosensitive. With these regimens, objective remission rates of more than 50% were recorded, including approximately 10% complete remissions (CRs). Moreover, some of these CRs were histopathologically confirmed. The finding that locally advanced disease (LAD) and technically unresectable disease could be rendered resectable by preoperative chemotherapy (EAP) was important. Thirty-six patients with LAD had been treated in a phase II trial with preoperative EAP, inducing 24 (70%) overall remissions (two clinical CRs, six pathologic CRs, 16 partial remissions [PRs] in 35 evaluable patients. Twenty-one patients were disease-free after chemotherapy with or without second-look surgery. The median survival time was 18 months for all patients and 24 months for disease-free patients. At 30+ months, 21% of all patients are still living disease-free. The expected survival of patients with unresectable LAD is approximately 4 to 6 months without any treatment and 6 to 9 months with standard chemotherapy. Compared with the latter results, the preoperative use of effective regimens (eg, EAP) seems to improve prognosis of patients with LAD. Moreover, such a multimodal approach may increase the number of long-term survivors among patients with resectable gastric cancer, especially those whose stage indicates a high risk of relapse (stages IIIa or IIIb). However, partly because of the severe toxicities (myelosuppression, nausea/vomiting), a considerable number of patients cannot be treated with these new regimens for the following reasons: Two of three patients with gastrointestinal disease are older than 60 years. Nontumorous diseases of the cardiovascular system, kidney, and others are frequent in this age group and may complicate or even prevent treatment with aggressive regimens. Considering the predominantly palliative treatment intentions in far advanced (metastasized) gastric cancer, regimens with low toxicities and acceptable activity should be preferred. For these reasons, we developed and investigated the combination ELF in a phase II trial in elderly patients (greater than 65 years) and in patients with cardiac risks who could not be treated with anthracyclines. The overall response rate in 51 evaluable patients was 53% (27 of 51) including six clinical CRs (12%). The median remission duration was 9.5 months and the median survival time was 11 months. Tolerability was excellent. Only 16% and 4% of patients, respectively, experienced WHO grades 3 and 4 leukopenia. Nausea/vomiting and mucositis/stomatitis were mild.(ABSTRACT TRUNCATED AT 400 WORDS)

Etoposide, leucovorin, 5-fluorouracil and interferon alpha-2b in elderly gastric cancer patients: a pilot study.

A total of 23 advanced gastric cancer patients older than 65 years received 500 mg/m2 5-fluorouracil i.v. on days 2-4, 120 mg/m2 vepesid i.v. on days 2-4, 150 mg/m2 6S-leucovorin on days 2-4, and 5 MU/m2 interferon alpha-2b on days 1-5, with cycles being repeated every 3 weeks. Toxicity was severe at an interferon (IFN) dose of 5 MU/m2; only one patient tolerated this dose. In 18 patients an IFN dose of 3 MU/m2 and in 3 other patients a dose of 4 MU/m2 could be given without producing toxicity. At an IFN dose of 5 MU/m2 the most common toxicities encountered were stomatitis (grade 4 in 1 patient and grade 3 in 12 patients), leukopenia (grade 4 in 1 patient and grade 3 in 5 patients), and thrombocytopenia (grade 3 in 3 patients). Two patients achieved a complete response and eight showed a partial response, resulting in an overall response rate of 45% [95% confidence interval (CI), 25%-64%]. The median survival was 7 months for all patients and 9 months for responding patients. In conclusion, without substantially increasing the toxicity, IFN can be added to the etoposide/leucovorin/5-fluorouracil combination, at a dose of 3 MU/m2. To verify the possible enhancement by IFN of the activity of this combination, a randomized trial is under way.