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At least 919 records · Page 51Linked to original sources
PubMed1998

Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee.

PURPOSE: D-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. METHODS: A group of 32 patients with refractory solid tumors completed 99 courses of D-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of D-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. RESULTS: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (Cmax) for D-limonene ranged from 10.8+/-6.7 to 20.5+/-11.2 microM. Predominant circulating metabolites were perillic acid (Cmax 20.7+/-13.2 to 71+/-29.3 microM), dihydroperillic acid (Cmax 16.6+/-7.9 to 28.1+/-3.1 microM), limonene-1,2-diol (Cmax 10.1+/-8 to 20.7+/-8.6 microM), uroterpenol (Cmax 14.3+/-1.5 to 45.1+/-1.8 microM), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of D-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. CONCLUSIONS: D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.

Adult↗
PubMed2006

Luteal-phase inhibin A and follicular-phase inhibin B levels are not characteristic of patients with an elevated LH-to-FSH ratio.

PURPOSE: To test whether serum inhibin levels are related to differences in gonadotropin concentrations between patients with an elevated LH-to-FSH ratio (ELF patients) and controls. METHODS: 32 ELF patients were matched with controls by age, body mass index (BMI), and cycle length. RESULTS: No statistically significant difference was found in follicular-phase inhibin B levels or midluteal inhibin A levels between cases and controls. Significant negative correlation was observed between follicular-phase inhibin B concentrations and BMI in ELF patients but not among controls. LH and FSH were positively related to inhibin B levels in ELF patients. Midluteal inhibin A correlated with sex hormone-binding globulin in controls but not in ELF patients. CONCLUSIONS: Neither follicular-phase inhibin B levels nor midluteal inhibin A levels are characteristic of patients with an elevated LH-to-FSH ratio. Opposite correlations with LH and BMI suggest dysregulation of inhibin secretion rather than dimeric inhibins having a central role to the endocrinological imbalance observed in polycystic ovary syndrome.

Adult↗
PubMed1992

Phase I/II study of external radio frequency phased array hyperthermia and external beam radiotherapy in the treatment of prostate cancer: technique and results of intraprostatic temperature measurements.

As part of an ongoing Phase I/II study at Duke University Medical Center investigating the toxicity and efficacy of external beam radiotherapy plus hyperthermia for deep-seated, locally advanced or recurrent solid tumors, 12 patients with prostate malignancies (adenocarcinoma--11, leiomyosarcoma--1) were treated with radiotherapy plus hyperthermia. Hyperthermia was given after radiotherapy using a Radio Frequency Phase/Amplitude Control Sigma 60 annular phased array device. All patients had simultaneous temperature measurements made in the rectal lumen and within the prostate during at least one hyperthermia session. Intraprostate thermometers were placed via a unique method described herein using both computerized tomography scan and a rigid sigmoidoscope for guidance. We were able to achieve the desired tumor temperature of > or = 42.5 degrees C in only 1/28 (3.5%) of hyperthermia treatments. Subjective symptoms of pain and/or pressure limited power deposition in 79% of hyperthermia treatments. Higher temperatures were achieved in the distal rectum than in the prostate in all treatments, although the differences were not statistically significant. This temperature differential could not be compensated by using phase and amplitude steering. Rectal temperatures adjacent to the prostate were predictive of prostate temperatures. We conclude that using this regional heating technique we were unable to demonstrate an ability to get an advantageous temperature differential between the prostate and normal tissue. This technique is not useful as an adjuvant to radiation therapy for prostate cancer. The usefulness of other regional heating techniques and devices should be explored.

Adenocarcinoma↗
PubMed2005

Late follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle.

This study examined serum glycodelin concentrations and endometrial expression during the luteal phase following oral administration of levonorgestrel (LNG) at different stages of the ovarian cycle. Thirty women were recruited and allocated into three groups. All groups were studied during two consecutive cycles, a control cycle and the treatment cycle. In the treatment cycle, each woman received two doses of 0.75 mg LNG taken 12 h apart on days 3-4 before the luteinizing hormone (LH) surge (Group 1), at the time of LH rise (Group 2) and 48 h after the rise in LH was detected (Group 3). Serum progesterone (P) and glycodelin were measured daily during the luteal phase, and an endometrial biopsy was taken at day LH +9 for immunohistochemical glycodelin-A staining. In Group 1, serum P levels were significantly lower, serum glycodelin levels rose earlier and endometrial glycodelin-A expression was weaker than in Groups 2 and 3, in which no differences were found between control and treatment cycles. Levonorgestrel taken for emergency contraception (EC) prior to the LH surge alters the luteal phase secretory pattern of glycodelin in serum and endometrium. Based on the potent gamete adhesion inhibitory activity of glycodelin-A, the results may account for the action of LNG in EC in those women who take LNG before the LH surge.

Adult↗
PubMed2002

S-phase kinase-associated protein 2 expression in non-Hodgkin's lymphoma inversely correlates with p27 expression and defines cells in S phase.

The protein expression of the cyclin-dependent kinase inhibitor p27 is often deregulated in human tumors. In lymphomas the inactivation of p27 is achieved through either increased degradation(1) or sequestration via D cyclins,(2) and p27 protein levels have been shown to have a prognostic significance.(1,3) Recently, S-phase kinase-associated protein 2 (Skp2) has been proved to mediate p27 degradation in normal cells(4-7) and to have oncogenetic properties.(8,9) In this study, B-, T-, and myeloid hematopoietic cell lines and a well-characterized panel of human lymphomas (n = 244) were studied for the expression of Skp2. In human lymphomas, the expression of Skp2 strongly related to the grade of malignancy, being low in indolent tumors and very high in aggressive lymphomas. Moreover, the percentages of Skp2- and S-phase-positive cells, as measured by DNA content or BrdU labeling, strictly matched and closely parallel that of Ki-67 and cyclin A. An inverse correlation between Skp2 and p27 was found in the majority of lymphoma subtypes. Nonetheless, most mantle cell lymphomas and a subset of diffuse large cell lymphomas failed to show this correlation, suggesting that alternative pathway(s) for the regulation of p27 might exist. The detection of Skp2 protein either by flow cytometry or by immunohistochemistry represents a simple method to precisely assess the S phase of lymphomas. The potential diagnostic and prognostic value of Skp2 is discussed.

Biomarkers↗
PubMed1998

Adrenergic receptors in premenstrual dysphoric disorder. II. Neutrophil beta2-adrenergic receptors: Gs protein coupling, phase of menstrual cycle and prediction of luteal phase symptom severity.

Abnormal beta2-adrenergic receptor coupling to Gs protein is implicated in depressive disorders. Steroid hormones and antidepressants modulate beta-adrenergic receptor coupling, which may relate to the therapeutic efficacy of antidepressants. We examined beta2-adrenergic receptors in 18 patients with premenstrual dysphoric disorder (PMDD), in 15 control subjects during the follicular phase and in 12 patients during late luteal phase. Antagonist-measured receptor density, agonist-measured receptor density in the high- and low-conformational states and agonist affinity to both states were measured. Coupling indices to Gs protein were determined from agonist-displacement experiments. Follicular beta2-adrenergic receptor density was higher in patients than in control subjects, with a trend for higher receptor density in the high-conformational state. The phase of menstrual cycle had no effect on beta2-adrenergic receptor regulation in PMDD. Exploratory correlations showed that the K(L)/K(H) ratio was related to anxiety ratings in control subjects and %R(H) was correlated with symptom severity in patients. In patients, follicular beta2-adrenergic receptor binding measures were correlated with luteal symptom severity. These findings suggest abnormal beta2-adrenergic receptor regulation in PMDD. Further exploration of the role of beta-adrenergic receptor kinase, sex steroid hormones and antidepressants on beta-adrenergic receptor regulation in PMDD is warranted.

Adult↗
PubMed2002

Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase.

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

Administration, Oral↗
PubMed2002

Abrogation of the S phase DNA damage checkpoint results in S phase progression or premature mitosis depending on the concentration of 7-hydroxystaurosporine and the kinetics of Cdc25C activation.

DNA damage causes cell cycle arrest in G(1), S, or G(2) to prevent replication on damaged DNA or to prevent aberrant mitosis. The G(1) arrest requires the p53 tumor suppressor, yet the topoisomerase I inhibitor SN38 induces p53 after the G(1) checkpoint such that the cells only arrest in S or G(2). Hence, SN38 facilitates comparison of p53 wild-type and mutant cells with regard to the efficacy of drugs such as 7-hydroxystaurosporine (UCN-01) that abrogate S and G(2) arrest. UCN-01 abrogated S and G(2) arrest in the p53 mutant breast tumor cell line MDA-MB-231 but not in the p53 wild-type breast line, MCF10a. This resistance to UCN-01 in the p53 wild-type cells correlated with suppression of cyclins A and B. In the p53 mutant cells, low concentrations of UCN-01 caused S phase cells to progress to G(2) before undergoing mitosis and death, whereas high concentrations caused rapid premature mitosis and death of S phase cells. UCN-01 inhibits Chk1/2, which should activate the mitosis-inducing phosphatase Cdc25C, yet this phosphatase remained inactive during S phase progression induced by low concentrations of UCN-01, probably because Cdc25C is also inhibited by the constitutive kinase, C-TAK1. High concentrations of UCN-01 caused rapid activation of Cdc25C, which is attributed to inhibition of C-TAK1, as well as Chk1/2. Hence, UCN-01 has multiple effects depending on concentration and cell phenotype that must be considered when investigating mechanisms of checkpoint regulation.

Alkaloids↗
PubMed2002

A phase II study of CI-980 in previously untreated extensive small cell lung cancer: an Ohio State University phase II research consortium study.

CI-980, (ethyl (S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b] pyrazine-7-yl) carbamate 2-hydroxyethansulfonate (1:1)), is a water-soluble mitotic inhibitor. It acts by binding to the colchicine-binding site on tubulin, a site different from that of the vinca alkaloids, inhibiting tubulin polymerization. Cells exposed to CI-980 accumulate in M phase and die. In preclinical tumor models, CI-980 showed a broad spectrum of activity, including in multi-drug resistant tumor cell lines, with activity at least equal to that of vincristine. Extensive small cell lung cancer, despite its responsiveness to chemotherapy, is usually an incurable disease with survival in patients of less than one year. Due to the preclinical activity of CI-980 and its similar mechanism of action to drugs effective in small cell lung cancer, a phase II trial in extensive small cell lung cancer was initiated by The Ohio State University Phase II Research Consortium. A "window of opportunity" design was chosen where a short six-week trial of the drug was given unless there was significant objective response. Twelve patients were entered in the study and underwent a total of 16 cycles of chemotherapy. The median age of the patients was 54 years old (range 34-71) and performance status was ECOG 0 (four patients), ECOG 1 (seven patients), and ECOG 2 (one patient). The patients were treated with a 72-hr infusion at a dose of 4.5 mg/m2/day. Toxicity was predominantly myelosuppression with granulocytopenia (nine episodes), and anemia (seven episodes). There were no objective responses with 11 patients being removed from study due to progressive disease. Evaluation of leukocyte microtubule structure in peripheral blood revealed microtubule depolymerization, which was seen after treatment (t = 72 hr) and was reversible within 24 hr of stopping the drug. We conclude that despite antitumor activity demonstrated in preclinical studies, CI-980 does not have biological activity in previously untreated small cell lung cancer at this dose and infusion protocol.

Adult↗
PubMed1996

Rationale for the dosage and schedule of CPT-11 (irinotecan) selected for phase II studies, as determined by European phase I studies.

BACKGROUND: CPT-11 (irinotecan), a camptothecin-derived anticancer agent with DNA topoisomerase 1 inhibitory activity, has demonstrated a broad spectrum of in vitro and in vivo activity in solid tumour models including multidrug-resistant tumours. This review details the rationale for the dosage schedule of CPT-11 selected for phase II studies, based on the results of 3 European phase I dose-escalating trials in patients with solid tumours. PATIENTS AND METHODS: CPT-11 was administered as a 30-minute intravenous infusion once every 3 weeks (schedule 1), once daily for 3 consecutive days every 3 weeks (schedule 2) or once weekly every 3 out of 4 weeks (schedule 3). RESULTS: Neutropenia and diarrhoea were the major dose-limiting toxicities in all of the studies. The maximum tolerated dose of CPT-11 was 115 and 145 mg/m2/day for schedules 2 and 3, respectively. With schedule 1, diarrhoea became dose-limiting at 350 mg/m2 but was manageable with high-dose loperamide therapy. CONCLUSIONS: CPT-11 350 mg/m2 administered as an intravenous infusion once every 3 weeks was chosen for further evaluation in early phase II studies, since this dosage regimen allowed the highest dose intensity with the least toxicity and was convenient for outpatient use. The place of higher doses (with intensive antidiarrhoeal support) and other administration schedules (e.g., protracted infusion) warrant further investigation.

Adolescent↗
PubMed1985

Hormonal profiles in the follicular phase, luteal phase and first trimester of pregnancies arising from in-vitro fertilization.

The hormonal profiles for oestradiol-17 beta, progesterone, prolactin and beta-human chorionic gonadotrophin (beta-hCG) are documented for the first 24 pregnancies arising from in-vitro fertilization during a collaborative project between the University of Western Australia and PIVET Laboratory. All patients had ovarian follicle stimulation with clomiphene citrate, sometimes combined with human menopausal gonadotrophin and all had oocyte recovery undertaken 36 h after injection of 5000 i.u. hCG. The follicular phase profile indicated that patients were admitted for the hCG injection when oestradiol-17 beta levels were around 1500 pmol/l per follicle with a dimension of greater than or equal to 1.6 cm on ultrasound. Luteal phase data indicated that oestradiol-17 beta and progesterone levels were two to three times higher than that expected during spontaneous conception cycles and those pregnancies which subsequently aborted had significantly lower levels in the late luteal phase. During pregnancy elevated oestradiol-17 beta and progesterone levels were maintained through the early weeks during organogenesis while the beta-hCG profile was similar to that reported for spontaneous pregnancies arising without ovarian stimulation. Six women aborted and the other 18 pregnancies have generated 22 infants.

Chorionic Gonadotropin↗
PubMed2002

Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study.

Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.

Adult↗
PubMed2005

GNOSIS: guidelines for neuro-oncology: standards for investigational studies-reporting of phase 1 and phase 2 clinical trials.

We present guidelines to standardize the reporting of phase 1 and phase 2 neuro-oncology trials. The guidelines are also intended to assist with accurate interpretation of results from these trials, to facilitate the peer-review process, and to expedite the publication of important and accurate manuscripts. Our guidelines are summarized in a checklist format that can be used as a framework from which to construct a phase 1 or 2 clinical trial.

Clinical Trials, Phase I as Topic↗
PubMed2005

Discrimination of cell nuclei in early S-phase, mid-to-late S-phase, and G(2)/M-phase by sequential administration of 5-bromo-2'-deoxyuridine and 5-chloro-2'-deoxyuridine.

5-Bromo-2'-deoxyuridine (BrdU) and 5-chloro-2'-deoxyuridine (CldU) were sequentially administered intraperitoneally into mice at 1-hr intervals. After one additional hr, the small intestines were resected, fixed, and embedded in paraffin. In histological sections stained with monoclonal antibody Br-3 reactive to both BrdU and CldU, and CldU antibody reactive only to CldU, three types of staining could be identified in the proliferating zone. Cells with nuclei stained only with Br-3 antibody were estimated to have completed DNA replication during the first 1 hr and were fixed in G(2)/M-phase. Those nuclei were frequently found in apical areas of the simple columnar epithelium of the intestine, whereas other nuclei were located basally in the cells. This observation suggested intracellular movement of cell nuclei in G(2)/M-phase. Identification of cells in early S-phase became possible using these antibodies in combination with DAB and fluorescence stainings. Replication sites in early S-phase nuclei were found to be numerous, whereas in late S-phase they were larger in size and much smaller in number.

Animals↗
PubMed2004

Efficacy and safety of imatinib mesylate for patients in the first chronic phase of chronic myeloid leukemia: results of a Japanese phase II clinical study.

Imatinib mesylate is a relatively new drug that targets the BCR-ABL chimeric protein, the molecular basis of chronic myeloid leukemia (CML). A phase II clinical trial in 39 Japanese patients in the first chronic phase of CML was conducted with imatinib mesylate at a dose of 400 mg/day. Hematologic complete response was obtained in 92.3% of the patients, complete cytogenetic response (CR) was obtained in 43.6%, and major partial CR was obtained in 20.5% of the patients. Although 29 of 39 patients required an adjustment of dosing because of grade 3 or 4 adverse events, most of the events were reversible, and 25 of the 29 patients were able to resume therapy. Between day 15 and day 35, grade 3 or 4 neutropenia and/or leukocytopenia occurred in 13 patients, and grade 3 thrombocytopenia occurred in 5 patients. Overall, nonhematologic grade 3 adverse events occurred in 28.2% of the patients. These data support the use of imatinib mesylate as the treatment of choice for chronic-phase CML patients.

Adult↗
PubMed1979

Gonadotropin in follicular phase in women with luteal phase defect.

Serum FSH and LH in women with luteal phase defect were measured. Their serum FSH and LH were lower than those in normal women and higher than those in women with amenorrhea. Administration of clomiphene citrate to the women with luteal phase defect were effective in 2/3 of the cases. These results are consistent with the hypothesis that a relative deficiency of FSH during the follicular phase results in diminished follicular development and subsequent inadequate corpus luteum maintenance.

Adult↗
PubMed1999

Gemcitabine and carboplatin in combination: an update of phase I and phase II studies in non-small cell lung cancer.

Gemcitabine has demonstrated single-agent activity in advanced, incurable non-small cell lung cancer, yielding response rates of > or =20%. In combination with cisplatin, response rates of 30% to 60% and encouraging survival have been observed. Carboplatin causes much less nonhematologic toxicity than cisplatin. In a phase III Eastern Cooperative Oncology Group trial, initial therapy with carboplatin yielded superior survival in advanced non-small cell lung cancer compared with cisplatin combinations and other cisplatin analogs, despite a lower response rate. Thus, studies designed to identify optimal dose schedules for a combination of gemcitabine plus carboplatin are clearly warranted. Carmichael et al from the United Kingdom have identified a maximum tolerated dose of carboplatin of area under the curve of 5.2 mg/mL/min administered on day I followed by gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. This combination produced a response rate of 31% and a median survival of 10.5 months in 13 evaluable patients. A subsequent phase I evaluation reversing the carboplatin and gemcitabine sequence (gemcitabine preceding carboplatin on day 1) demonstrated no difference in toxicities, pharmacodynamics, or maximum tolerated dose. Other investigators have identified similar promising results with this regimen, although one North American investigator has observed untoward toxicity in a small number of patients using a standard 28-day dose schedule with gemcitabine administered on days, 1, 8, and 15. Day-15 gemcitabine dosing is problematic and may contribute to excessive thrombocytopenia when gemcitabine is combined with carboplatin. The ongoing phase I/II trials reviewed here have focused on a compressed 21-day schedule, with carboplatin administered every 3 weeks and gemcitabine given on days 1 and 8 only.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

A phase I-phase II study of vinorelbine with cisplatin, 5-fluorouracil, and leucovorin for advanced non-small cell lung cancer.

PURPOSE: The combination of cisplatin, 5-fluorouracil, and leucovorin (PFL) has been reported to have a 29% response rate in advanced non-small cell lung cancer. Vinorelbine, a semi-synthetic vinca alkaloid, has also been reported to have single-agent activity in this disease. We designed a phase I-II study in which escalating doses of vinorelbine were added to PFL to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine, and to determine the response rate and survival at the recommended phase II dose. PATIENTS AND METHODS: This study enrolled patients between December 1991 and August 1993. Eligibility criteria included histologically or cytologically documented stage III or IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 20 mg/m2) on days 1 and 6, cisplatin 100 mg/m2 on day 2, and 5-fluorouracil as a continuous infusion at 800 mg/m2/day for 4 days (days 2-5) with leucovorin 100 mg orally every 4 hours on days 1 through 5. Cycles were repeated every 21 days. RESULTS: Forty patients were treated during the study. The median age of the patients was 58 (range, 33-75) and 36 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in both patients treated with vinorelbine at 25 mg/m2. At the recommended phase II vinorelbine dose of 20 mg/m2 on days 1 and 6, myelosuppression remained the most common toxicity, with 22 patients (55%) having grade 4 neutropenia. Fifteen patients (38%) required hospital admission for neutropenic fever; two died of neutropenic sepsis. Of 33 patients evaluated, 2 patients achieved a complete response and 10 patients achieved a partial response (overall response rate, 30%; 36% of the evaluated patients). Median survival was 10.4 months for the entire cohort (16.4 months for those with stage III disease and 9.6 months for patients with stage IV disease) and 1-year survival was 45%. The overall median time to progression was 8.1 months. CONCLUSIONS: The maximum tolerated dose of vinorelbine given on days 1 and 6 with PFL is 20 mg/m2; myelosuppression is the dose-limited factor. The response rate is similar to rates observed in prior studies of combination chemotherapy, but the median survival of patients with stage IV disease exceeds that of many other regimens.

Adenocarcinoma↗