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E Raymond

Publications and source records attributed to E Raymond.

At least 73 records · Page 4Linked to original sources
PubMed1999

Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin.

CPT-11, a DNA topoisomerase I inhibitor, and oxaliplatin, a diaminocyclohexane platinum derivative, are cytotoxic agents that have demonstrated clinical antitumor activity in colorectal cancer. Given the therapeutic potential of their combination, we studied the cellular pharmacology of SN-38, the active metabolite of CPT-11, and oxaliplatin in the human colon cancer HT29 cell line. Growth inhibition was studied after a 1- or 24-h exposure to SN-38 or oxaliplatin, given alone or in combination. The cytotoxicity analysis by the isobolograms method elicited synergy. SN-38 delayed the reversion of oxaliplatin-induced DNA interstrand cross-links (ISCs), measured in cells by alkaline elution. The amount of detectable ISCs 15 h after a 1-h exposure to 10 microm oxaliplatin was 27% of the ISC peak levels and increased to 68% in the presence of 0.1 microM SN-38. The presence of oxaliplatin DNA adducts led to a 3.3-fold increase in the SN-38-induced DNA elongation inhibition, as measured by pulse-labeling alkaline elution. Inhibition of DNA and RNA synthesis was longer after exposure to the combination of oxaliplatin and SN-38 than after exposure to each agent alone. Consistently, flow cytometry analyses revealed that preexposure to oxaliplatin enhanced SN-38-induced S-phase arrest. Filter binding assays indicated that the cells arrested in S-phase at 48 h were undergoing apoptosis. Hence, supra-additive cytotoxicity appears related to major modifications in the cellular response to DNA damage rather than to changes in DNA damage formation. The combination of CPT-11 and oxaliplatin induced a 2-fold higher tumor growth reduction in vivo than did oxaliplatin alone at feasible nonlethal doses. This study provides a rationale for the optimal use of CPT-11 and oxaliplatin in combination.

Adenocarcinoma↗
PubMed1999

[Rapamycin and CCI-779].

Rapamycin (sirolimus) is a macrolide, related to cyclosporine with immunosuppressive properties and antiproliferative activity in various human tumor cells lines and tumor xenograft models. The cytosolic kinase mTOR which controls the initiation of the translation of messenger RNA is the main known target of rapamycin. During clinical studies, rapamycin given by oral route as immunosuppressant did not show dose-limited toxicity and only asymptomatic thrombopenia and hyperlipemia were observed. In murine models, best antitumoral activity was observed using parental routes. CCI-779, an analog formulated for intravenous use has antitumor activity without significant immunosuppressive property in mice and is currently in phase I trials in man.

Administration, Oral↗
PubMed1999

Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos.

Cationic porphyrins, which interact with guanine quadruplex (G4) telomeric folds, inhibit telomerase activity in human tumor cells. In this study, we have further examined effects of porphyrins and other telomere- and telomerase-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyrins: (i) TMPyP4, a potent telomerase inhibitor; and (ii) TMPyP2, an isomer of TMPyP4 and an inefficient telomerase inhibitor, azidothymine (AZT), the reverse transcriptase inhibitor, antisense phosphorothioate oligonucleotide to telomerase RNA (TAG6) and a control scrambled sequence (ODN). TMPyP4, AZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferation and increased the percentage of cells trapped in mitosis. Nuclear localization of TAG6, but not of ODN, was demonstrated with 5'-fluoresceinated analogs of TAG6 and ODN. Formation of elongated chromosomes incapable of separating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phenotypes resulting from telomerase template mutation or dominant negative TRF2 allele. Our data suggest that G4-interactive agents exert their antiproliferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.

Animals↗
PubMed1998

Dimethyl sulfoxide (DMSO) causes a reversible inhibition of telomerase activity in a Burkitt lymphoma cell line.

INTRODUCTION: Telomerase is an enzyme that is required for maintenance of telomeres. This enzyme has been shown to be present in germline tissues and majority of tumors and tumor cell lines. The regulation of telomerase is an area of active investigation in different models because, potentially, inhibition of this enzyme could be important in cancer therapy. To study the regulation of this enzyme in lymphoma cell lines, we used DMSO to produce a reversible G0/G1 arrest in Raji cell line, as shown earlier [Sawai M, Takase K, Teraoka H, Tsukada K. Reversible G1 arrest in the cell cycle of human lymphoid cell lines by dimethyl sulphoxide. Exp Cell Res 1990;187:4-10]. METHODS: In this study, we use a highly quantifiable conventional (non-amplified) assay to study the effect of DMSO on telomerase. In addition, we studied cellular proliferation and cell cycle profiles of the cells treated and, subsequently, released from DMSO induced blockage. RESULTS: In this model, DMSO reversibly inhibited telomerase activity that could be restored after release from the blockage. The inhibition of telomerase seems to parallel cellular proliferation and it appears that telomerase is regulated upon entry into the cell cycle. This view is consistent with other previously published views on relationship of telomerase with exit from cell cycle. CONCLUSION: Our observations demonstrate a novel effect of DMSO on cellular mechanisms in Raji cell line. It may provide an attractive model to further study regulation of telomerase in this cell line.

Burkitt Lymphoma↗
PubMed1998

Oxaliplatin: a review of preclinical and clinical studies.

Of the new generation platinum compounds that have been evaluated, those with the 1,2-diaminocyclohexane carrier ligand-including oxaliplatin--have been focused upon in recent years. Molecular biology studies and the National Cancer Institute in vitro cytotoxic screening showed that diaminocyclohexane platinums such as oxaliplatin belong to a distinct cytotoxic family, differing from cisplatin and carboplatin, with specific intracellular target(s), mechanism(s) of action and/or mechanism(s) of resistance. In phase I trials, the dose-limiting toxicity of oxaliplatin was characterized by transient acute dysesthesias and cumulative distal neurotoxicity, which was reversible within a few months after treatment discontinuation. Moreover, oxaliplatin did not display any, auditory, renal and hematologic dose-limiting toxicity at the recommended dose of 130 mg/m2 q three weeks or 85 mg/m2 q two weeks given as a two-hour i.v. infusion. Clinical phase II experiences on the antitumoral activity of oxaliplatin have been conducted in hundreds of patients with advanced colorectal cancers (ACRC). Single agent activity reported as objective response rate in ACRC patients is 10% and 20% overall in ACRC patients with 5-fluorouracil (5-FU) pretreated/refractory and previously untreated ACRC, respectively. Synergistic cytotoxic effects in preclinical studies with thymidylate synthase inhibitors, cisplatin/carboplatin and topoisomerase I inhibitors, and the absence of hematologic dose-limiting toxicity have made oxaliplatin an attractive compound for combinations. Phase II trials combining oxaliplatin with 5-FU and folinic acid ACRC patients previously treated/refractory to 5-FU showed overall response rates ranging from 21% to 58%, and survivals ranging from 12 to 17 months. In patients with previously untreated ACRC, combinations of oxaliplatin with 5-FU and folinic acid showed response rates ranging from 34% to 67% and median survivals ranging from 15 to 19 months. Two randomized trials totaling 620 previously untreated patients with ACRC, comparing 5-FU and folinic acid to the same regimen with oxaliplatin, have shown a 34% overall response rate in the oxaliplatin group versus 12% in the 5-FU/folinic acid group for the first trial; and 51.2% vs. 22.6% in the second one. These statistically significant differences were confirmed in time to progression advantage for the oxaliplatin arm (8.7 vs. 6.1 months, and 8.7 vs. 6.1 months, respectively). A small but consistent number of histological complete responses have been reported in patients with advanced colorectal cancer treated with the combination of oxaliplatin with 5-FU/folinic acid, and secondary metastasectomy is increasingly done by oncologists familiar with the combination. Based on preclinical and clinical reports showing additive or synergistic effects between oxaliplatin and several anticancer drugs including cisplatin, irinotecan, topotecan, and paclitaxel, clinical trials of combinations with other compounds have been performed or are still ongoing in tumor types in which oxaliplatin alone showed antitumoral activity such as ovarian, non-small-cell lung, breast cancer and non-Hodgkin lymphoma. Its single agent and combination therapy data in ovarian cancer confirm its non-cross resistance with cisplatin/carboplatin. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent.

Animals↗
PubMed1998

In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients.

BACKGROUND: Ecteinascidin-743 (ET-743), a member of the ecteinascidin family selected for clinical development, is a tetrahydroisoquinolone alkaloid isolated from the marine ascidian, Ecteinascidia turbinata. This novel compound is a minor groove binding, guanine-specific alkylating agent which also interacts with the microtubule network and blocks cell cycle progression at late S/G2. MATERIALS AND METHODS: A soft agar cloning assay was used to determine the in vitro effects of ET-743 against primary human tumor specimens taken directly from patients. A total of 93 evaluable specimens were exposed to ET-743 for one-hour (n = 25) and/or 14-day continuous exposure (n = 92) at concentrations ranging from 0.1 nM to 1 microM. In vitro responses were defined as an inhibition > or = 50% of human tumor colony forming units at a given concentration. RESULTS: One-hour exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM induced in vitro responses in 0% (0/17), 6% (1/17), 16% (4/25), 13% (1/8), and 25% (2/8) of specimens, respectively. Continuous exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM, inhibited 0% (0/16), 13% (2/16), 49% (44/90), 62% (47/76), and 77% (58/75) of tumor specimens, respectively. Tumor-specific responses and concentration-dependent relationships were observed with a continuous exposure to ET-743. At 100 nM, the compound inhibited 79% (11/14) breast, 69% (9/13) non-small-cell lung, 58% (7/12) ovary, and 88% (7/8) melanoma specimens. At 1 microM, ET-743 inhibited 100% (14/14) breast specimens, 85% (11/13) non-small-cell lung, 67% (8/12) ovary and 86% (6/7) melanoma specimens. Activity of ET-743 at and above 10 nM was also observed against sarcoma and kidney tumors. At 10 nM concentration and continuous exposure ET-743 demonstrated incomplete cross-resistance with paclitaxel, alkylating agents, doxorubicin and cisplatin. CONCLUSIONS: Our data from the cloning assay indicate that the duration of exposure to ET-743 is an important factor in human tumors. Therefore, long-term exposure to ET-743 may be preferred in future clinical trials. The activity of ET-743 in breast, non-small-cell lung, and ovarian cancers as well as in melanoma may deserve further clinical evaluations. The potential of ET-743 in sarcoma and renal tumors might also be considered. In addition, our data indicate that a plasma concentration of 100 nM of ET-743 must be considered as a target during the clinical development of the compound; also the concept of continuous/protracted exposure in clinical trials with ET-743 has to be taken into account.

Animals↗
PubMed1998

Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen.

BACKGROUND: FOLFOX2, a bimonthly regimen of high-dose leucovorin (LV), 48-hour continuous infusion of 5-fluorouracil (5-FU) (LV-5-FU) and oxaliplatin (100 mg/m2) produced a high response rate (46%; 95% confidence interval (95% CI): 31%-60%) in 5-FU pre-treated patients with metastatic colorectal cancer. In this phase II study, pre-treated patients were given a lower dose of oxaliplatin to reduce the toxic effects of the regimen. PATIENTS AND METHODS: Thirty patients with advanced colorectal adenocarcinoma and progression while receiving bimonthly LV-5-FU (LV: 500 mg/m2, 5-FU: 1.5-2 g/m2/22 hours, days 1-2, every two weeks), were given the same LV-5-FU schedule with the addition of oxaliplatin (85 mg/m2) every two weeks (FOLFOX3). RESULTS: The main toxic effects were peripheral neuropathy (90%) with four severe sensitive neuropathies (WHO grade 2: 13%). The response rate was 20% (95% CI: 8%-39%). Median progression-free survival was 26 weeks, median survival was 57 weeks from the start of FOLFOX3 and median duration of the response was 37 weeks. CONCLUSIONS: Results obtained with FOLFOX3 confirmed the synergy between oxaliplatin and 5-FU in 5-FU-resistant metastatic colorectal cancer. However, the response rate seems to be lower than that obtained with FOLFOX2. Further studies to determine the best oxaliplatin dose intensity are in progress.

Adenocarcinoma↗
PubMed1998

Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies.

Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.

Adolescent↗
PubMed1998

Antiproliferative effects of recombinant human bone morphogenetic protein-2 on human tumor colony-forming units.

Bone morphogenetic protein-2 (BMP-2) is a differentiation factor for normal osteoblasts. BMP-2 is structurally related to transforming growth factor-beta which inhibits cell proliferation and enhances apoptosis. A recent study has shown the presence of BMP-2 receptors on several cancer cell lines. In this study, we attempted to determine if recombinant human BMP-2 (rhBMP-2) can modulate the proliferation of human tumor colony-forming units taken from 113 patients. Tumor cells were cultured in soft agar and continuously exposed to three concentrations of rhBMP-2 (10, 100 and 1000 ng/ml) for 14 days in the capillary cloning system. There were 65 evaluable specimens, including 17 breast cancers, 15 ovarian cancers, 14 non-small cell lung cancers and five prostate cancers. Importantly, rhBMP-2 did not stimulate the tumor cell proliferation. A significant inhibition (50% or less survival of tumor colony-forming units) was seen in 16 of 65 specimens (24.6%) at 1000 ng/ml, including five of 14 non-small cell lung cancers, five of 17 breast tumors and two of 15 ovarian tumors. A concentration-response relationship was observed (p<0.001 by Mantel-extension test). The results of this study encourage further evaluation of the antiproliferative effects of rhBMP-2 against human cancers.

Bone Morphogenetic Protein 2↗
PubMed1998

Activity of oxaliplatin against human tumor colony-forming units.

This study was conducted to identify tumor types warranting Phase II clinical trials of oxaliplatin using the human tumor cloning assay. Oxaliplatin was tested at concentrations ranging from 0.5 to 50.0 microg/ml in 1-h and 14-day continuous exposures along with 1.4 microg/ml carboplatin and 0.2 microg/ml cisplatin for comparison. We defined in vitro response as tumor growth inhibition >50% of control. In the 1-h exposure schedule, in vitro responses were observed in 9 of 116 (8%), 18 of 115 (16%), 38 of 103 (37%), and 7 of 13 (54%) tumor specimens at concentrations of 0.5, 5.0, 10.0, and 50.0 microg/ml oxaliplatin, respectively. In the 14-day exposure schedule, in vitro responses were observed in 10 of 121 (8%), 37 of 121 (31%), 57 of 106 (54%), and 15 of 15 (100%) tumor specimens at concentrations of 0.5, 5.0, 10.0, and 50.0 microg/ml oxaliplatin, respectively. Activity was observed against colon cancer, non-small cell lung cancer, gastric cancer, and melanoma colony-forming units. In both cisplatin-resistant and cisplatin-sensitive tumors, the activity of oxaliplatin was concentration and time dependent. A 1-h exposure to 5.0 and 10.0 microg/ml oxaliplatin led to 7.4 and 23.4% in vitro responses, respectively, in specimens resistant to 1-h exposure of 0.2 microg/ml cisplatin. Moreover, 1-h exposures to 5.0 microg/ml and 10.0 microg/ml oxaliplatin showed in vitro antitumor responses in 10.2 and 24.3%, 17.2 and 34.5%, 10.0 and 20.0%, 6.7 and 16.7%, and 11.4 and 34.3% of specimens resistant to 1.4 microg/ml carboplatin, 6.0 microg/ml 5-fluorouracil, 3.0 microg/ml irinotecan, 10.0 microg/ml paclitaxel, and 0.04 microg/ml doxorubicin, respectively. The effect in those drug-resistant specimens was improved when oxaliplatin was used on the protracted exposure regimen. Our data indicate that oxaliplatin is an active drug in vitro against a large variety of human tumors. Both concentration and duration of exposure are important factors for oxaliplatin cytotoxicity. The broad spectrum of activity and the in vitro activity against some tumors primarily resistant to conventional anticancer drugs encourage further clinical investigations of oxaliplatin in patients with advanced cancer refractory to conventional chemotherapy.

Antineoplastic Agents↗
PubMed1998

Oxaliplatin: mechanism of action and antineoplastic activity.

Oxaliplatin, a platinum-based chemotherapeutic agent with a 1,2-diaminocyclohexane (DACH) carrier ligand, has shown in vitro and in vivo efficacy against many tumor cell lines, including some that are resistant to cisplatin and carboplatin. The retention of the bulky DACH ring by activated oxaliplatin is thought to result in the formation of platinum-DNA adducts, which appear to be more effective at blocking DNA replication and are more cytotoxic than adducts formed from cisplatin. Studies by the National Cancer Institute (NCI) have suggested that oxaliplatin has a spectrum of activity different from that of either cisplatin or carboplatin, suggesting that it has different molecular targets and/or mechanisms of resistance. Oxaliplatin has been demonstrated to differ in some mechanisms associated with the development of cisplatin resistance. Compared with cisplatin-conditioned cells, deficiencies in mismatch repair (MMR) and increases in replicative bypass, which appear to contribute to cisplatin resistance, have not been shown to induce a similar resistance to oxaliplatin. A decreased likelihood of resistance development makes oxaliplatin a good candidate for first-line therapy. Studies also demonstrate additive and/or synergistic activity with a number of other compounds, however, suggesting the possible use of oxaliplatin in combination therapies.

Animals↗
PubMed1998

[Irinotecan: various administration schedules, study of drug combinations, phase I experience].

Irinotecan (CPT11) is a synthetic camptothecin-derived DNA topoisomerase I inhibitor. Based on phase I clinical trials, several schedules have been recommended for phase I studies including 350 mg/m2 every 3 weeks in Europe, 125 mg/m2 for 4 weeks every 6 weeks in the USA, and 100 mg/m2 weekly or delayed until recovery in case of grade > 2 toxicity in Japan. The principal dose-limiting toxicities in those schedules are neutropenia and delayed diarrhea. Early treatment with high doses of loperamide has made diarrhea a manageable toxicity and allowed dose escalation up to 500 mg/m2. Recently, two very interesting schedules have been investigated allowing to increase dose-intensity: every other week infusion and protracted infusion. With those schedules, it appears that the diarrhea occurred more frequently with the weekly schedule. In addition, authors have observed interpatients variations in terms of toxicity and pharmacokinetics. Those variations may be related to modifications in the hepatic metabolism of the drug that may occur in patients with hepatic dysfunction and/or in patients with concomitant medications. The understanding of the individual metabolism of the drug would help to determine individual dose adaptation. Based on synergistic preclinical interaction with several drugs, combinations of irinotecan with other cytotoxic drugs such as thymidylate synthethase inhibitors and platinum salts are currently investigated in phase I-II studies.

Administration, Oral↗
PubMed1997

Bimonthly high dose leucovorin and 5-fluorouracil 48-hour infusion with interferon-alpha-2a in patients with advanced colorectal carcinoma. Groupe d'Etude et de Recherche sur les Cancers de l'Ovaire et Digestifs (GERCOD).

UNLABELLED: BACKGROUND; The rationale for the modulation of 5-fluorouracil (5-FU) with interferon-alpha (IFN) is inhibition of 5-FU catabolism and 5-FU resistance. Clinical trials have shown debatable results when IFN is given in high doses with 5-FU used as a bolus alone or in combination with leucovorin (LV). A first-line Phase II study was performed in 50 patients with metastatic colorectal carcinoma who were given a bimonthly combination of high dose LV, a high dose 48-hour infusion of 5-FU, and a low dose of IFN. METHODS: The regimen was comprised of a 2-hour infusion of LV, 500 mg/m2, on each of 2 consecutive days, and a 48-hour infusion of 5-FU, 1.5 to 2 g/m2/24 hours, starting after Day 1 of LV treatment every 2 weeks until there was evidence of disease progression. IFN was administered subcutaneously three times weekly at a dose of 3 MU (body surface area [BSA] < 1.75 m2) or 4.5 MU (BSA > OR = 1.75 m2). RESULTS: World Health Organization toxicity Grade 3-4 occurred in 21 patients (42%): diarrhea in 6%, mucositis in 12%, neutropenia in 30%, and alopecia in 8%. The overall response rate was 44%; 1 patient had a complete response (2%), 21 had partial responses (42%), 23 had stable disease (46%), and 5 had disease progression (10%). The median progression free survival was 9 months, and median survival was 25 months. CONCLUSIONS: Bimonthly high dose LV, a high dose 48-hour infusion of 5-FU, and a low dose of IFN had good activity in patients with advanced colorectal carcinoma. However, as in other schedules of LV and 5-FU, IFN induces high grade toxicity.

Adenocarcinoma↗
PubMed1997

Bimonthly high dose leucovorin and 5-fluorouracil 48-hour continuous infusion in patients with advanced colorectal carcinoma. Groupe d'Etude et de Recherche sur les Cancers de l'Ovaire et Digestifs (GERCOD).

BACKGROUND: It has been suggested that there is a relationship between 5-fluorouracil (5-FU) dose levels and response rates. A bimonthly 2-day regimen of leucovorin (LV) and 5-FU bolus plus infusion has been found to be superior to a monthly 5-FU bolus with low dose LV. Based on these reports, a first-line Phase II study was performed in 101 patients with advanced colorectal carcinoma who were given a bimonthly combination of high dose LV and a high dose 48-hour infusion of 5-FU. METHODS: The selected regimen included a 2-hour infusion of LV, 500 mg/m2, on each of 2 consecutive days and a 48-hour infusion of 5-FU, 1.5 to 2 g/m2/24 hours starting after Day 1 of LV treatment every 2 weeks until there was evidence of disease progression. Evaluation was performed every six cycles. This study reports the treatment of 101 patients with measurable disease. RESULTS: World Health Organization toxicity Grade 3-4 occurred in 15% of patients, nausea in 2%, diarrhea in 5.1%, mucositis in 4%, neutropenia in 4% (Grade 4: 2%), hand-foot syndrome in 2%, alopecia in 4%, and encephalopathy in 1%. The overall response rate was 33.7%. Five patients had a complete response (5%), and 29 had a partial response (28.7%). In 45 patients disease was stable (44.6%), and in 19 patients there was disease progression (18.8%). Three patients (3%) could not be evaluated. The median progression free survival was 8 months and median survival was 18 months. CONCLUSIONS: In the current study, bimonthly high dose LV and a high dose 48-hour infusion of 5-FU had activity in patients with advanced colorectal carcinoma. Toxicity is notably low, and the regimen is suitable for use in combination with other drugs.

Adenocarcinoma↗
PubMed1997

[Modulation of 5-fluorouracil with folinic acid in advanced colorectal cancers. Groupe d'étude et de recherche sur les cancers de l'ovaire et digestifs (GERCOD)].

The rational of leucovorin modulation of 5-fluorouracil and the clinical results in colorectal cancer are reviewed with special emphasis on the monthly schedule of low dose leucovorin and 5FU bolus for 5 consecutive days (NCCTG-Mayo Clinic regimen) and the bimonthly schedule of high-dose leucovorin and 5FU bolus plus continuous infusion for two consecutive days (LV5FU2) which is now considered as a new standard.

Antidotes↗
PubMed1997

[Oxaliplatin, folinic acid and 5-fluorouracil (folfox) in pretreated patients with metastatic advanced cancer. The GERCOD].

Preliminary studies suggest synergy between oxaliplatin and fluorouracil (5-FU). To assess this issue, we performed a study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. Regimen consisted of oxaliplatin day 1, 130 mg/m2 every two cycles (folfox 1) or 100 mg/m2/cycle (folfox 2) or 85 mg/m2/cycle (folfox 3) and leucovorin 500 mg/m2 as a 2-hour infusion, followed by 5-FU 22 h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. One hundred and thirteen patients have been treated. One complete response (CR) and 32 partial responses (PRs) were observed for an overall response rate of 29.2%. Sixty-seven patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU than the one used in the folfox regimens, among them 18 had PRs (26.9%). The best response rate was observed in patients treated with the folfox 2 regimen: 41.7%. From start of folfox, median progression-free survival was 6 months and median survival 13 months. Limiting toxicities were peripheral neuropathy and neutropenia. Fifty-four percent of the patients experienced WHO toxicity > or = grade 3 with the folfox1 regimen, 45% with the folfox2 and 40% with the folfox3. The folfox regimens achieve a high response rate in pretreated patients with CRC. Further studies are needed to determine the best oxaliplatin dose-intensity.

Adult↗
PubMed1997

Long-term follow-up after adjuvant chemotherapy in completely resected early stage ovarian carcinoma.

OBJECTIVE: To evaluate the impact of standardized staging, surgery and adjuvant chemotherapy on survival of patients with completely resected early ovarian carcinoma. STUDY DESIGN: We performed a multicentric retrospective analysis of 283 patients with early stage ovarian carcinoma consecutively treated between 1977 and 1993. Borderline tumours were excluded. A comprehensive staging was performed during initial laparotomy. Patients were treated by standardized surgical resection and all excepted stage IA received a 6-course adjuvant chemotherapy. RESULTS: Eighty patients were excluded because of incorrect substaging, inadequate surgery and adjuvant therapy. The analysis was performed on 203 patients with completely resected early stage ovarian cancer (139, stage I; 64, stage II). Relapse-free survival and overall survival rates for stage I were 66 and 69%, respectively. Relapse-free survival and overall survival rates for stage II were 57 and 61% respectively. Median time of relapse was 18 months (range, 1-107 months). Sites of relapse were peritoneum (45%), retroperitoneal lymph nodes (37%) and distant metastases (18%). Relapses occurring within 18 months had a median survival after relapse of 9 months while later relapses had a median survival of 22 months (P = 0.005). There was no significant difference in relapse-free and overall survival according to the age, performance status and pathology. Cisplatin-based chemotherapy improved the 10-year overall survival of patients with stage IIB and IIC as compared to chemotherapy without cisplatin (oral melphalan. CMF regimen); 91 vs. 33% (P = 0.012) and 75 vs. 42% (P = 0.05), respectively. Cisplatin-based regimens did not improve survival in stage IA, IB and IIA. CONCLUSIONS: Early ovarian cancers have a good prognosis after comprehensive staging, complete surgery and adjuvant chemotherapy. Cisplatin-based regimens compared to melphalan and CMF showed a significant increase of survival in stage IIB and IIC. Prognosis of relapse depends on the relapse-free interval duration.

Adult↗