gimeracil and Carcinoma--Non-Small-Cell-Lung

Invasive thymoma (IT) and thymic carcinoma (TC) are rare epithelial neoplasms arising in the anterior mediastinum. Platinum-based chemotherapies are widely used for first-line treatment of unresectable IT and TC, but no standard treatment has been established for previously-treated IT and TC thus far. Because promising efficacy of S-1 (tegafur, gimeracil and oteracil combination) has been reported in some retrospective studies, we conducted the first prospective phase II trial to evaluate its efficacy in previously-treated patients with advanced IT and TC.. Patients progressing after at least one regimen of systemic chemotherapy received S-1 orally at a dose based on body surface area for 2 weeks followed by one week of rest until tumor progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity profile. We defined an ORR of 25% as indicating potential usefulness while ORR of 10% was the lower limit of interest.. Forty patients were enrolled (IT, n = 20; TC, n = 20). ORR was 17.5% (95% CI 7.3-32.8; IT, 10%; TC, 25%), disease control rate was 85% (IT, 95%; TC, 75%). Median PFS was 7.0 months (IT, 11.3 months; TC, 5.4 months), and median OS was 40.3 months (IT, 58.5 months; TC, 22.7 months) with a median follow-up of 51.9 months. Major toxicities (grade 3-4) were anorexia (10%), neutropenia (7.5%) and pneumonitis (5%). No treatment-related death was observed.. Although the primary endpoint was not met, S-1 monotherapy did have effects similar to recently reported immunotherapies for TC but at much lower cost. S-1 could represent a treatment option for previously-treated advanced TC. This trial was registered as UMIN 000008174.

Topics: Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Follow-Up Studies; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Oxonic Acid; Prognosis; Prospective Studies; Pyridines; Survival Rate; Tegafur; Thymoma; Thymus Neoplasms

The aim of this multicenter study was to determine the appropriate administration schedule for S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological-Stage IA (tumor diameter, 2-3 cm) non-small-cell lung cancer.. Patients were randomly assigned to receive adjuvant chemotherapy consisting of either the 4-week oral administration of S-1 (80-120 mg/body/day) followed by a 2-week rest (Group A), or the 2-week oral administration of S-1 (80-120 mg/body/day) followed by a 1-week rest (Group B). The duration of adjuvant chemotherapy was 1 year in both arms. The primary endpoint was compliance, namely drug discontinuation-free survival, which was calculated using the Kaplan-Meier method with log-rank test.. Eighty patients were enrolled in this study, and 76 patients actually received S-1 treatment. The drug discontinuation-free survival rates at 1 year were 49.1% in Group A and 52.7% in Group B (P = 0.373). The means of the relative dose intensities were 55.3% in Group A and 64.6% in Group B (P = 0.237). There were no treatment-related deaths. Patients with grade 3/4 toxicities were significantly more frequent in Group A (40.5%) than in Group B (15.4%, P = 0.021). The 2-year relapse-free survival rates were 97.5% in Group A and 92.5% in Group B, and the 2-year overall survival rates were 100% in both groups.. The feasibility showed no significant difference between the two groups among patients with completely resected Stage IA (tumor diameter, 2-3 cm) non-small-cell lung cancer.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oxonic Acid; Pyridines; Survival Rate; Tegafur; Treatment Outcome

S-1, an oral fluoropyrimidine, is usually given for 4 weeks (80 mg/m2/day) followed by a 2-week rest. However, compliance with this regimen is unsatisfactory because of adverse events such as leukopenia, anorexia, and nausea. To reduce adverse effects and improve compliance, we studied a "5-day on/2-day off" low-dose regimen of S-1 and evaluated pharmacokinetics in patients with non-small-cell lung cancer (NSCLC).. Twelve patients with NSCLC were divided into 2 groups and received S-1 in a dose of 25 mg twice daily (level 1, n = 6) or 40 mg twice daily (level 2, n = 6) for 5 consecutive days followed by a 2-day rest (5 days on/2 days off) every week. Plasma 5-fluorouracil (5-FU) concentrations were measured.. The maximum concentration in plasma and the area under the plasma concentration-time curve from 0 to 9 h were respectively 55.3 ± 21.1 ng/ml and 290.2 ± 95.7 ng·hr/ml for level 1, as compared with 104.2 ± 33.5 ng/ml and 541.9 ± 232.3 ng·hr/ml for level 2. These values were similar to those previously reported for a continuous intravenous infusion of 5-FU. Adverse events were grade 1 fatigue (n = 1 in each group) and anorexia (n = 1 in each group).. A "5-day on/2-day off" low-dose (40 mg twice daily) regimen of S-1 is feasible for the treatment of NSCLC, with acceptable plasma 5-FU concentrations and minimal adverse effects. A phase II or III trial of this regimen in an adjuvant setting is warranted in patients with NSCLC.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Drug Combinations; Female; Follow-Up Studies; Gas Chromatography-Mass Spectrometry; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Patient Compliance; Pyridines; Tegafur; Treatment Outcome

We report the development of spinal infarction during adjuvant chemotherapy with tegafur, gimeracil and oteracil (TS-1) after surgery for lung adenocarcinoma. A 69-year-old female had a left upper lobectomy for pulmonary adenocarcinoma, T2aN0M0. Six weeks after the surgery, tegafur, gimeracil and oteracil were administered orally as adjuvant chemotherapy for 1 year. After 10 months of adjuvant chemotherapy, the patient suddenly showed signs of numbness and weakness in both lower limbs. The patient did not have a previous medical history, and was receiving only tegafur, gimeracil and oteracil with the stomach medication. Neurological findings showed muscle weakness, numbness and a loss of tendon reflex in both lower limbs, as well as bladder and rectal disturbance. Blood tests, brain magnetic resonance imaging and chest computed tomography showed no signs of abnormalities or metastasis. Magnetic resonance imaging of the spine showed a hyperintense lesion between the Th12 and L1 spinal levels by T2-weighted image. A spinal fluid test indicated no abnormalities, and cytological diagnosis was class II. Anti-aquaporin 4, anti-ganglioside and anti-neuronal autoantibodies were all negative. These results indicated that the patient had a spinal infarction, rather than myelitis or paraneoplastic neurological syndrome. The patient was treated with heparin and steroid pulse treatment followed by rehabilitation, and recovered sufficiently to be able to walk using a cane after 2 months. The development of spinal infarction during anti-cancer chemotherapy has not been previously reported. In this case, an association of spinal infarction with the use of adjuvant chemotherapy was strongly indicated due to the lack of abnormalities in coagulability, atherosclerotic lesions and aortic disease.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Female; Humans; Infarction; Lung Neoplasms; Oxonic Acid; Pneumonectomy; Pyridines; Spinal Cord; Tegafur; Treatment Outcome

A 61-year-old woman with recurrent non-small cell lung cancer presented with thrombocytopenia, microangiopathic hemolytic anemia, neurological abnormalities, renal failure and a fever that appeared during chemotherapy with gemcitabine and bevacizumab. She was diagnosed with drug-induced thrombotic thrombocytopenic purpura (TTP). After the discontinuation of chemotherapy, the administration of recombinant human soluble thrombomodulin and fresh-frozen plasma rapidly ameliorated the TTP. Hypertension preceded the onset of TTP and required the administration of quadruple therapy on admission. However, after three months, the hypertension was controllable without anti-hypertensive drugs. Twelve months later, the ninth course of vinorelbine was administered safely, preventing the patient's lung cancer from progressing.

Topics: Acute Kidney Injury; Antibodies, Monoclonal, Humanized; Antihypertensive Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Cisplatin; Combined Modality Therapy; Deoxycytidine; Docetaxel; Erlotinib Hydrochloride; Female; Gemcitabine; Glutamates; Guanine; Humans; Hypertension; Lung Neoplasms; Middle Aged; Oxonic Acid; Pemetrexed; Plasma; Purpura, Thrombotic Thrombocytopenic; Pyridines; Quinazolines; Recombinant Proteins; Solubility; Taxoids; Tegafur; Thrombomodulin

The expressions of thymidylate synthase (TS) and intracellular metabolic enzymes have been reported to be associated with the sensitivity and/or resistance to 5-fluorouracil (5-FU). However, since the role of these enzymes in the mechanism of resistance to 5-FU has not been fully examined in lung cancer, in the present study we measured the expression levels of TS, dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT) genes in lung cancer cell lines by real-time PCR, and the sensitivity to 5-FU using the MTS assay. The expression of DPD was significantly correlated with the concentration of 5-FU for 50% cell survival in 15 non-small-cell lung cancer (NSCLC) cell lines (p<0.05), but the expressions of TS, TP, and OPRT were not. Treatment with 5-chloro-2,4-dihydroxypyridine, an inhibitor of DPD, altered the sensitivity to 5-FU in DPD-expressing RERF-LC-MT cells, indicating that modulation of DPD activity could increase the 5-FU sensitivity in lung cancer. In contrast, TS expression was dramatically higher in a 5-FU-resistant small-cell lung cancer cell line than in the parent cell line, whereas the expressions of DPD, TP, and OPRT genes were not markedly different. In order to examine the effect of other cytotoxic agents on TS and DPD expression, we compared the expressions of both genes between cisplatin-, paclitaxel-, gemcitabine-, or 7-ethyl-10-hydroxycamptothecin-resistant lung cancer cells and their respective parent cells, but found no differences between any pair of resistant subline and the corresponding parent cell line. Our results indicate that degradation of 5-FU due to DPD is an important determinant in 5-FU sensitivity, while induction of TS contributes to acquired resistance against 5-FU in lung cancer. Therefore, the expression levels of TS and DPD genes may be useful indicators of 5-FU activity in lung cancer.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Camptothecin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Cisplatin; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Humans; Inhibitory Concentration 50; Irinotecan; Lung Neoplasms; Paclitaxel; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Thymidylate Synthase