Phase I trial of UFT/leucovorin and irinotecan in patients with advanced cancer.

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.

Phase I clinical and pharmacogenetic trial of irinotecan and raltitrexed administered every 21 days to patients with cancer.

PURPOSE: Irinotecan and raltitrexed display schedule-dependent synergy in vitro, which supports the clinical investigation of the combination. Functional polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene result in intracellular redistribution of folate derivatives, which may affect raltitrexed-associated cytotoxicity. PATIENTS AND METHODS: Patients with a range of solid cancers and good performance status received irinotecan as a 90-minute infusion on day 1 and raltitrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples were collected for MTHFR C677T genotyping and fasting plasma homocysteine during the first cycle. RESULTS: Thirty-nine assessable patients received 127 cycles of therapy. Irinotecan doses ranged from 100 to 350 mg/m(2), and raltitrexed, 1.0 to 4.0 mg/m(2). Raltitrexed doses of more than 3.0 mg/m(2) were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevation. Irinotecan/raltitrexed doses of 350/3.0 mg/m(2) were well-tolerated; principal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancers. Homozygotes with the MTHFR 677 TT polymorphism incurred significantly less raltitrexed-associated toxicity than those with either wild-type or heterozygous genotypes (P = .05). No significant differences were noted in plasma homocysteine values between the genotypic subtypes, and plasma homocysteine levels did not predict the risk of toxicity. CONCLUSION: Irinotecan and raltitrexed doses of 350 and 3.0 mg/m(2) are recommended for further study on a day 1, 2 schedule every 21 days. Efficacy results suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitrexed toxicity.

A phase I trial of topotecan and gemcitabine administered weekly for 3 consecutive weeks to patients with advanced tumors.

BACKGROUND: The complementary action of gemcitabine and topotecan on DNA metabolism suggested the potential for their use in combination chemotherapy. Gemcitabine, a synthetic cytidine analogue chain terminator, and topotecan, a topoisomerase-1 inhibitor, have been reported to have broad antitumor activity and are approved for clinical use. METHODS: The cytotoxicity of the combination in various models in vitro was additive. In the current study, the authors conducted a Phase I study to determine the recommended Phase II doses and toxicity profile of gemcitabine and topotecan when administered weekly in combination. Gemcitabine (400--1000 mg/m(2)) was given intravenously over 30 minutes followed by a 15-minute infusion of topotecan (0.75--2.5 mg/m(2)) weekly for 3 consecutive weeks in a 4-week treatment cycle. Thirty-eight patients with advanced refractory solid tumors and good performance status were treated. RESULTS: Myelosuppression in the form of granulocytopenia and thrombocytopenia were the major dose-limiting toxicities. Other toxic effects included anemia, nausea, and elevated hepatic transaminases. Partial responses were observed in two patients (one with nonsmall cell lung carcinoma and one with pancreatic carcinoma). Disease stabilization occurred in five patients (three with pancreatic carcinoma, one with rectal carcinoma, and one with metastatic carcinoma of an unknown primary site). Gemcitabine, 1000 mg/m(2), and topotecan, 2.5 mg/m(2), were the maximum tolerated doses for this combination. CONCLUSIONS: The results of the current study showed that the combination of weekly gemcitabine and topotecan for 3 weeks in a 4-week cycle schedule appeared to be well tolerated and was associated with clinical activity. Therefore, this combination is recommended for a further Phase II evaluation.

Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma.

PURPOSE: As therapy for locally advanced non-small-cell lung carcinoma (NSCLC) improves, brain metastases (BM) may become a greater problem. We analyzed our chemoradiation experience for patients at highest risk for the brain as the first failure site. METHODS: Records for 150 consecutive patients with stage II/III NSCLC treated definitively with chemoradiation from June 1992 to June 1998 at the University of Pennsylvania were reviewed. Most patients (89%) received cisplatin, paclitaxel, or both. All had negative brain imaging before treatment. Posttreatment brain imaging was performed for suspicious symptoms. Incidence of BM was examined as a function of age, sex, histology, stage, performance status, weight loss, tumor location, surgery, radiation dose, initial radiation field, chemotherapy regimen, and chemotherapy timing. RESULTS: Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (P <.04) versus stage II/IIIA. Histology alone was not significant (P <.12), although patients with IIIB nonsquamous tumors had an exceptionally high 2-year BM rate of 42% (P <.01 v all others). Examining treatment-related parameters, crude and 2-year actuarial risk of BM were 27% and 39%, respectively, in patients receiving chemotherapy before radiotherapy and 15% and 20%, respectively, when radiotherapy was not delayed (P <.05). On multivariate analysis, timing of chemotherapy (P <.01) and stage IIIA versus IIIB (P <.01) remained significant. CONCLUSION: Patients with later stage, nonsquamous NSCLC, particularly those receiving induction chemotherapy, have sufficiently common BM rates to justify future trials including prophylactic cranial irradiation.

Pilot study of organ preservation multimodality therapy for locally advanced resectable oropharyngeal carcinoma.

The purpose of this study was to determine the early efficacy and toxicity of a new multimodality organ-preservation regimen for locally advanced, resectable oropharyngeal squamous cell carcinoma (SCC). Patients with T3-4N0-3M0 or T2N2-3M0 oropharyngeal SCC were eligible for this Phase II study. Patients needed the physiologic reserve for surgery and technically resectable tumors. Induction carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) x 2 cycles (q21 days) were given. Objective responders received definitive radiotherapy (XRT), 70 Gy/7 weeks with concurrent weekly paclitaxel. Initially, the dose of paclitaxel was 50 mg/m2/week; because of mucosal toxicity it was reduced to 30 mg/m2/week. Patients with N2-3 disease received post-XRT neck dissection and 2 more cycles of "adjuvant" chemotherapy. In the first 22 patients, the neutropenic fever rate was 27%. Although there has been no grade IV-V toxicity from induction therapy, grade II-III toxicity resulted in an unacceptable delay in starting XRT in 14% of patients. The response rate to induction chemotherapy was 91%. Grade III mucositis occurred in all patients during concurrent chemoradiotherapy. One patient died of pneumonia during concurrent chemoradiotherapy after receiving 26 Gy and 3 doses of paclitaxel 50 mg/m2. No dose-limiting toxicity occurred in 15 patients treated with concurrent paclitaxel 30 mg/m2/week. Actuarial overall survival at 18 months is 82%; local-regional control is 86%. To date, distant metastases have not developed in any patients. This regimen has intense but acceptable acute toxicity. The maximum tolerated dosage of weekly paclitaxel during standard continuous-course XRT is confirmed to be 30 mg/m2/week. The treatment efficacy of this regimen (response rate and short-term local-regional and distant control) is encouraging. Accrual continues to obtain long-term toxicity, efficacy, and quality-of-life data.

Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer.

PURPOSE: To identify factors that may predict for severe radiation pneumonitis or pneumonopathy (RP), we reviewed a set of simple, commonly available characteristics. METHODS AND MATERIALS: Medical records of 148 lung cancer patients with good performance status (ECOG 0-1) treated definitively with chemoradiation from 6/92-6/98 at the University of Pennsylvania were reviewed. Actuarial survival and the crude rate of severe radiation pneumonitis were determined as a function of several variables. Potential predictive factors examined included age, gender, histology, stage, pulmonary function, performance status (0 vs. 1), weight loss, tumor location, radiation dose, initial radiation field size, chemotherapy regimen, and timing of chemotherapy. Univariate analysis (log-rank test) was performed for each variable. Multivariate analysis was performed using linear regression. RESULTS: Median survival for the entire cohort was 14.7 months. Four patients were inevaluable for pneumonitis due to early death from progressive disease. Of the remaining 144 evaluable patients, 12 (8.3%) experienced severe RP. The most significant factor predicting for severe RP was performance status (p < 0.003). The risk of severe RP was 16% for PS-1 patients vs. 2% for PS-0 patients. Women were significantly more likely to develop severe RP than men (p = 0.01). Among 67 patients for whom pre-radiation therapy pulmonary function data were available, forced expiratory volume of the lung in 1 second (FEV(1)) was also significant (p = 0. 03). No patient suffering severe RP had a pretreatment FEV(1) > 2.0 liters. The median radiation dose was 59.2 Gy and median initial radiation field size was 228 cm(2). Neither radiotherapy factor predicted for RP. Other factors studied, including chemotherapy drugs, and schedule, also were not significant predictors of severe RP. CONCLUSIONS: Pretreatment performance status, gender, and FEV(1) are significant predictors of severe radiation pneumonopathy, at least when using conventional radiation fields and doses. Complex radiation dose-volume algorithms that attempt to predict lung complication probabilities should probably incorporate these simply obtained clinical parameters.

A phase I study of WR-2721 in combination with total body irradiation (TBI) in patients with refractory lymphoid malignancies.

This Phase I study was designed to establish the maximum tolerated dose (MTD) of WR-2721 when given twice weekly with total body irradiation (TBI) in the treatment of patients with advanced refractory lymphoid malignancies and to define the toxicities of this combination and schedule. Patients eligible for this study had advanced recurrent indolent non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Patients had symptomatic or progressive disease, a performance status of 0, 1, or 2, and adequate bone marrow, hepatic, and renal function. Only patients failing one or two regimens of prior chemotherapy were eligible. Patients who had received prior extended field irradiation were ineligible. Patients received TBI twice weekly (Tuesday and Friday) to a total of 10 doses at 15 cGy/fx. WR-2721 was given intravenously over 15 min beginning 30 min before irradiation. The escalation of WR-2721 was Level 1: 740 mg/m2 and Level 2: 910 mg/m2. The MTD of WR-2721 was that dose which produced predictable and reversible toxicity and would not interfere with patient well-being. Seven patients were entered onto the study, three at 740 mg/m2 and four at 910 mg/m2. Five patients had CLL and two patients small lymphocytic NHL. No patient had hypotension or nausea requiring reduction in dose level or even interruption of infusion of WR-2721. At 740 mg/m2 no grade 3 or 4 toxicities related to WR-2721 were observed, but two patients could not complete treatment because of TBI-induced prolonged thrombocytopenia following treatments 5 and 8. One patient completed all 10 treatments. At 910 mg/m2 of WR-2721, two patients requested removal from study because of malaise, one after 5 cycles and one after 7 cycles. One patient completed all 10 treatments. One patient was treated with a modified schedule of 7 treatments of 20 cGy/fx and tolerated and completed all treatments but developed significant thrombocytopenia following completion of treatment. No patients had disease progression during treatment. The median survival was 11 months. This study indicates that WR-2721 given at 910 mg/m2 twice weekly with TBI is well tolerated for at least 5 treatments and that 910 mg/m2 of WR-2721 is the MTD with this regimen. In view of the importance of total radiation dose in achieving a response with TBI, a dose escalation study of TBI with 910 mg/m2 of WR-2721 should be performed in patients with indolent non-Hodgkin's lymphoma.

Partial purification of thrombopoietin from the plasma of thrombocytopenic rabbits.

Partially purified thrombopoiesis-stimulating activity was prepared from the plasma of thrombocytopenic rabbits using ammonium sulfate precipitation and DEAE cellulose, Sephadex, and carboxymethyl cellulose chromatography. The protein fraction precipitated by an ammonium sulfate saturation of 60%-80%, previously shown to contain thrombopoiesis-stimulating activity, was used as starting material. Column chromatography was carried out at room temperature at pH 5.6. Under these conditions, thrombopoiesis-stimulating activity (thrombopoietin) was retained by DEAE cellulose (0/03 M citrate-phosphate buffer) and carboxymethyl cellulose (0/003 M citrate-phosphate buffer), and eluted with 0.4 M NaCl. Thrombopoietin was retarded by Sephadex G-100; the ratio of the elution volume to the void volume was 1.32:1. Immunoelectrophoretic analysis of partially purified thrombopoietin indicated that following removal of most of the albumin by DEAE chromatography, only proteins with the mobilities of beta-globulins and albumin and traces of other anodally migrating proteins were detectable in the fractions that contained thrombopoiesis-stimulating activity. Thrombopoietin was not dialyzable and was stable from at least pH 5.6 to 7.5. It was approximately 1000-fold purified following sequential chromatography with DEAE and carboxymethyl cellulose. Although the three fractions described reproducibly stimulated thrombopoiesis, as measured by increased levels of selenomethionine-75Se (75SeM) in the circulating platelets, platelet counts did not increase.

Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy.

A technique of quantitative venography has been developed in which values are assigned to the deep veins of the calf, knee, thigh, and pelvis, based upon the calculated volume and degree of occlusion of these venous segments. A maximum score of 40 units reflects complete thrombosis of all segments. This technique has been applied to a randomized, single-blind study of streptokinase versus heparin treatment. Each group of 12 patients had similar mean inital venographic scores; follow-up venograms were performed 5 days after the start of therapy. Streptokinase patients with high initial scores (larger than 20) showed a mean improvement of 12.1 units, while those with low initial scores(less than 20) were essentially unchanged. Heparin patients with high scores had a minimal mean improvement of 1.1 units, but those with low scores had a significant mean extension of thrombosis of 8.6 units. Patients with symptoms for less than 7 days showed greated mean improvement (12.7 units) with streptokinase that those with a longer duration of symptoms (2.0 units); heparin patients in these subgroups showed a mean worsening of 7.5 units and no change, respectively. Extrinsic venous obstruction by tumor did not prevent an excellent response to streptokinase. No single test of coagulation of fibriolysis was a reliable indicator of the degree of venographic response to lytic therapy. Pyrexia and hemorrhagic complications occurred in over one-half of the streptokinase patients; one had an anaphylactic reaction, and one died of intracerebral hemorrhage during therapy. The data suggest that lytic therapy is best restricted to the patient with acute extensive thrombosis. Also, continuous infusions of heparin according to current guidelines may be inadequate to prevent thrombus growth in some patients.