Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus.

BACKGROUND: The aim of the study was to evaluate the efficacy and tolerability of the combination of oxaliplatin, fluorouracil and leucovorin in patients with advanced esophagus cancer. PATIENTS AND METHODS: Thirty-five patients with recurrent or metastatic esophageal adenocarcinoma or squamous cell carcinoma were enrolled. Up to one prior chemotherapy regimen was allowed. All patients had bi-dimensionally measurable disease. Patients received oxaliplatin 85 mg/m2 as a 2-h infusion on day 1. Leucovorin (500 mg/m2) followed by fluorouracil bolus (400 mg/m2) and 22-h continuous infusion fluorouracil (600 mg/m2) was administered on days 1 and 2. Granulocyte colony stimulating factor was not routinely administered unless the patient developed febrile neutropenia or prolonged neutropenia. Treatment was repeated every 14 days. RESULTS: Of the thirty-five patients enrolled, all were evaluated for toxicity and 34 were evaluated for response. The overall response rate was 40% (95% confidence interval, 24% to 57%) with complete and partial response rates of 3% and 37%, respectively. The median response duration was 4.6 months, and the median overall survival was 7.1 months. One-year survival was 31%. The major toxicity noted was cumulative neutropenia, with 29% developing grade 4 toxicity. There was one treatment-related death secondary to neutropenic sepsis. The most common non-hematologic toxicity encountered with this regimen was cumulative peripheral neuropathy, with 26% experiencing grade 2 or 3 toxicity. CONCLUSIONS: The combination of oxaliplatin, leucovorin, and fluorouracil shows significant anti-tumor activity and a favorable toxicity profile in patients with metastatic carcinoma of the esophagus.

A phase II study of oxaliplatin and paclitaxel in patients with advanced non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy and toxicity of oxaliplatin and paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The treatment regimen was given as defined in a phase I investigation in patients with previously treated ovarian cancer. It consisted of paclitaxel 175 mg/m(2) (1-h infusion) and oxaliplatin 130 mg/m(2) (2-h infusion) given every 21 days. Eligible patients had stage IIIB (pleural effusion)/IV NSCLC, measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic function. RESULTS: A total of 38 patients were enrolled with the following characteristics: 29% male (n = 11); 71% female (n = 27); median age 64.5 years (range 37-78); performance status of 0-1 84% (n = 32); stage IIIB 8% (n = 3); stage IV 92% (n = 35). One hundred and eighty-one cycles were administered, with a median of four per patient (range one to 12). The overall objective response rate for all 38 patients was 34.2% [95% confidence interval (CI) 19.6% to 51.4%]. This response rate includes 13 patients who met criteria for a partial response. No complete responses were observed. Median overall survival time was 9.2 months (95% CI 6-12.4) and median progression-free survival time was 4.3 months (95% CI 2.1-6.5). The 1- and 2-year overall survival rates were 37% and 21%, respectively. Hematological toxicity included six patients with grade 4 neutropenia. Non-hematological toxicity consisted mainly of grades 1 and 2 neurosensory toxicity. Laryngodysesthesia was observed in two patients following oxaliplatin infusion. No grade 4 non-hematological toxicities were encountered. CONCLUSION: This regimen is well tolerated, and demonstrates activity in patients with advanced NSCLC.

Phase I/II investigation of paclitaxel, ifosfamide and carboplatin for advanced non-small-cell lung cancer.

BACKGROUND: The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. PATIENTS AND METHODS: Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m(2) as a 1-h infusion on day 1 with carboplatin at an area under the concentration-time curve (AUC) of 6 mg.min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m(2) on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m(2) on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg.ml/min. Therapy for dose levels I and III included filgrastim support (5 micro g/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/ micro l. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen's activity and tolerability. RESULTS: Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. CONCLUSIONS: The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.

A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer.

BACKGROUND: Chemorefractory small-cell lung cancer (SCLC) is defined as disease that progresses during primary therapy or within 3 months of completion of primary therapy. Patients with chemorefractory SCLC have a very poor prognosis, and no treatment has been shown to be of significant clinical benefit. Elevated expression of Bcl-2 is found in the majority of SCLCs and has been associated with therapeutic resistance. Suppression of Bcl-2 levels through the use of G3139, an antisense oligonucleotide complementary to the mRNA encoding Bcl-2, might increase the antitumor efficacy of cytotoxic therapy. PATIENTS AND METHODS: Twelve patients with chemorefractory SCLC participated in this pilot trial of paclitaxel combined with G3139. G3139 was given by continuous i.v. infusion over 7 days at a fixed dose of 3 mg/kg/day. Paclitaxel dose was initially 175 mg/m2 on day 6, but was decreased to 150 mg/m2 due to myelosuppression observed in two of the three patients treated in the first dose cohort. RESULTS: The combination of paclitaxel at 150 mg/m2 and G3139 at 3 mg/kg/day was found to be feasible and well tolerated. No objective responses were observed, but two patients had stable disease, one remaining stable on therapy for >30 weeks. Plasma G3139 levels were determined, and were found to be highest in the patient with prolonged stable disease, suggesting that individual variation in metabolism and clearance of the antisense oligonucleotide may influence activity. CONCLUSIONS: This study demonstrates that G3139 can be combined with paclitaxel in a cytotoxic dose range, and suggests that a similar combination be tested for activity in the context of chemoresponsive disease.

A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest.

JM216 is an orally administered platinum analogue. We undertook this study to determine the maximally tolerated dose (MTD) of JM216 when administered with concomitant radiotherapy to the chest (200 cGy daily, 5 x/week) in patients with locoregionally advanced non-small cell lung (NSCLC) or esophageal cancer. Patients were excluded for inadequate bone marrow reserve, prior radiotherapy to the primary tumor or previous treatment with platinum drugs. A dose-limiting toxicity (DLT) was defined using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) and consisted of grade > or = 2 renal, hepatic, cardiac, or pulmonary toxicity or grade > or = 3 hematologic, neurological, or gastrointestinal toxicity. A total of 23 patients were registered; two never received treatment and are excluded from analyses. Six patients were treated at a dose of 30 mg/m2/day for 5 days with two grade 2 DLT's: cough (1 pt) and elevated trans-aminases (1 pt). Seven evaluable patients were treated at 60 mg/m2/day and seven experienced grade 3 or 4 toxicity, five related to myelosuppression. The dose was then reduced to 45 mg/m2/d. Eight patients were evaluable for toxicity, of which 5 experienced DLT: myelosuppression (3 pts), esophagitis (2 pts), dyspnea (1 pt), and elevated creatinine (1 pt). Fourteen patients were evaluable for efficacy, of which 6 had an objective response, including one complete response. The recommended phase II dose of JM216 with concurrent radiation therapy is 30 mg/m2/d for 5 days. The major DLT is myelosuppression with only limited increased toxicity within the field of radiation. This conceivably may limit the use of JM216 as a radiation sensitizer.

A phase II trial of 9-aminocaptothecin (9-AC) as a 120-h infusion in patients with non-small cell lung cancer.

In a previous phase II trial of the synthetic topoisomerase I inhibitor, 9-aminocamptothecin (9-AC), given as a 72-h infusion, we identified modest single agent activity of 9% in patients with previously untreated advanced non-small cell lung cancer (NSCLC). Preclinical studies suggested that a more prolonged continuous infusion of the drug might lead to greater antitumor activity. A phase I study recommended a phase II dose of 25 microg/m2/hr for 120 h (3000 microg/m2 over 5 days), administered for 2 consecutive weeks of a 3-week cycle. We utilized this schedule and enrolled 13 chemotherapy-naïve patients with Stage IIIB and IV NSCLC in this trial: median age 67 (range 57-74); 46% male; 92% stage IV; and median performance status 1. Twelve patients are available for response and toxicity evaluation after 2 cycles of therapy. One patient achieved a partial response. Four patients had stable disease while seven patients had progressive disease. Patients with stable or progressive disease after two cycles received no additional 9-AC, and were offered conventional chemotherapy. The median survival time was 10.2 months and the one-year survival rate 28% (95% confidence interval, 5-58%). Significant toxicities included myelosuppression, fatigue, and anorexia. One patient had grade 4 neutropenia following the first week of cycle 2, and did not receive additional therapy. There were no neutropenia-related infections. These data suggest that this prolonged schedule is unlikely to increase 9-AC's very modest activity in NSCLC above that seen with the simpler 72-h administration schedule. Further evaluation of 9-AC in NSCLC is not recommended.

Phase I study of pegylated liposomal doxorubicin, paclitaxel, and cisplatin in patients with advanced solid tumors.

BACKGROUND: The combination of doxorubicin, paclitaxel, and cisplatin has activity in gynecologic malignancies but requires colony stimulating factor (G-CSF) support. Moreover, there is concern about cardiotoxicity with doxorubicin/paclitaxel combinations. Pegylated liposomal doxorubicin may result in less myelosuppression and cardiac toxicity than free doxorubicin. The purpose of this study was to determine the maximal tolerated dose of pegylated liposomal doxorubicin with fixed doses of paclitaxel and cisplatin without using G-CSF support in advanced solid malignancies. PATIENTS AND METHODS: Twenty-three patients were enrolled; none of the patients had received prior doxorubicin. Patients received paclitaxel (90 mg/m2 for dose level one, escalating to 135 mg/m2 for all subsequent dose levels), with a fixed dose of cisplatin (60 mg/m2), followed by escalating doses of pegylated liposomal doxorubicin every 21 days. RESULTS: A total of 73 cycles was administered. Grade 4 neutropenia was seen after cycle one in two of eight patients receiving 30 mg/m2 of pegylated liposomal doxorubicin and three of seven patients receiving 40 mg/m2 of pegylated liposomal doxorubicin when combined with 135 mg/m2 of paclitaxel and 60 mg/m2 of cisplatin. Two additional patients at the 40 mg/m2 dose level developed grade 4 neutropenia following cycles 2 and 5. The mean decline in left ventricular ejection fraction (LVEF) after 2 cycles was 5 percentage points (P = 0.012). CONCLUSION: The combination of pegylated liposomal doxorubicin, paclitaxel and cisplatin is feasible without G-CSF support.

Lung cancer.

Lung cancer remains a major worldwide health problem, accounting for more than a sixth of cancer deaths. The proportion of cancers that are adenocarcinomas is increasing in North America and to some degree in Europe, leading to a changing clinical picture characterised by early development of metastases. Newer diagnostic techniques have allowed for more accurate tumour staging and treatment planning. In patients with non-small-cell cancer, surgical resection offers substantial cure rates in early-stage cases. Combined chemotherapy plus radiation therapy has clearly improved the treatment results for patients with locally advanced cancers, and patients with metastatic disease are now candidates for newer chemotherapy regimens with more favourable results than in the past. Small-cell lung cancer is highly responsive to chemotherapy, and recent advances in radiation therapy have improved the prospects for long survival. New techniques for screening, and innovative approaches to both local and systemic treatment offer hope for substantial progress against this disease in the near future.

A phase I study of STEALTH cisplatin (SPI-77) and vinorelbine in patients with advanced non small-cell lung cancer.

STEALTH cisplatin (SPI-77) is a liposomal formulation of cisplatin that has activity in animal models of non small-cell lung cancer (NSCLC). Vinorelbine has documented clinical activity in NSCLC. The purpose of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of SPI-77 when administered in combination with a fixed dose of vinorelbine to patients with stage IIIB or IV NSCLC refractory to or recurrent following previous chemotherapy. SPI-77 was given on day 1 in combination with vinorelbine at a fixed dose of 25 mg/m2 on days 1 and 8 of a 3-week treatment cycle. Dose escalation of SPI-77 progressed as follows: 20, 40, 80, 100, 120, and 140 mg/m2. Twenty patients were entered (11 men and nine women; median age, 63 years). Sixty-four complete cycles of therapy were administered, and 19 of 20 patients completed at least 1 cycle of combination chemotherapy. Neutropenia was dose limiting at a SPI-77 dose of 140 mg/m2. Neuropathy and nephrotoxicity were minimal and not dose related. A partial response was observed in three of 17 patients eligible for a response evaluation and response duration ranged from 6 weeks to 5 months. In conclusion, treatment with combination SPI-77 and vinorelbine was well tolerated, and our recommended phase II dose is 120 mg/m2 of SPI-77 in combination with vinorelbine at 25 mg/m2. Activity was observed in this patient population, and additional phase II testing of this regimen in a less extensively pretreated cohort of patients with NSCLC is indicated.

Therapeutic plasma exchange for the acute management of the catastrophic antiphospholipid syndrome: beta(2)-glycoprotein I antibodies as a marker of response to therapy.

We describe two patients with the catastrophic antiphospholipid syndrome associated with elevation of beta(2)-glycoprotein I antibodies and fulminant thrombotic diatheses. Both patients were treated with therapeutic plasma exchange (TPE), which resulted in a marked decrease in antibody titer accompanied by an improved clinical outcome in one patient (IgG antibody). In the second patient, the outcome was poor despite TPE (IgA antibody). There were no significant complications of TPE in either case. Because of the fulminant nature of the catastrophic antiphospholipid syndrome, we conclude that a trial of TPE is warranted for the acute management. Further studies are needed to clarify which patients may benefit from this treatment.

First two cases of immune hemolytic anemia associated with ceftizoxime.

BACKGROUND: Second- and third-generation cephalosporins have been associated with immune-mediated hemolytic reactions. This report discusses two patients who developed clinically significant extravascular hemolysis while receiving the third-generation cephalosporin ceftizoxime (Ceftizox). This is believed to be the first time hemolysis has been described in patients receiving this drug. STUDY DESIGN AND METHODS: Immunologic workup of drug-dependent antibodies was performed on blood samples using drug-coated and immune complex methodologies. Antibody classes and titers were analyzed. RESULTS: Both the patients' sera contained anti-ceftizoxime that reacted with red cells only when ceftizoxime was added to the sera ("immune complex" method). The patients recovered without complications following discontinuation of the drug. Each patient had IgM and IgG drug-dependent antibodies. The drug-induced antibodies from each patient cross-reacted with cefotaxime, which is structurally similar to ceftizoxime, but cross-reacted either weakly or not at all with ceftriaxone, which has a more complex side chain. CONCLUSION: This report describes the first cases of immune hemolytic anemia associated with ceftizoxime. In drug-induced hemolytic reactions, prompt recognition and discontinuation of the drug may be important factors in reducing the chance of serious sequelae.

Combined modality therapy in non-small cell lung and esophageal cancer: a phase I dose-escalation study of docetaxel with concurrent radiotherapy.

The effective treatment of non-small cell lung cancer requires both locoregional and systemic therapy. Outcome in intermediate-stage malignancies of the chest may be improved by combining chemotherapy and radiotherapy. Several combined-modality trials involving the platinum compounds, vinorelbine, gemcitabine, and the taxanes have been recently conducted. In one such phase I dose-escalation study of 29 patients with non-small cell lung cancer or esophageal cancer, the concurrent administration of docetaxel and radiotherapy at a dose of 2 Gy/d for 6 weeks was shown to be feasible. Objective tumor responses were observed, and further studies of docetaxel in combination with radiotherapy are indicated.

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer.

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

Ifosfamide-based three-drug combination regimens in non-small cell lung cancer.

The role of chemotherapy in the treatment of non-small cell lung cancer (NSCLC) has expanded in recent years, resulting in increased median survival and higher 5-year survival rates in some studies. Few patients with NSCLC can be cured, however, and the median survival time is still modest. Research strategies are aimed at identifying new active single agents, testing their combination in non-cisplatin- and non-carboplatin-containing regimens, and their incorporation into regimens containing more than two drugs, in efforts to improve response and survival and/or reduce toxicity. Several trials of triplet chemotherapy combinations for the treatment of NSCLC have been conducted at the University of Chicago. The three-drug regimen of vinorelbine, paclitaxel, and ifosfamide with granulocyte colony-stimulating factor was evaluated in a phase I trial. Doses of all three drugs were reduced from their standard doses so that toxicity would be manageable, although toxicity was still high. The low response rate (<20%) at the recommended phase II doses led to early closure of this trial. The University of Chicago is also assessing the three-drug combination of carboplatin, paclitaxel, and ifosfamide in patients with stage IIIB and IV NSCLC. The carboplatin and paclitaxel doses are being maintained within their active single-agent range, with the goal of identifying the maximum tolerated dose of ifosfamide when added to this combination. Additional end points include response rates, survival time, and dose-limiting toxicities. This study is ongoing.

Phase I study of docetaxel with concomitant thoracic radiation therapy.

PURPOSE: The taxanes have demonstrated activity as radiation sensitizers in preclinical studies. This study was designed to determine the maximum-tolerated dose (MTD), optimal schedule, and toxicities of docetaxel in combination with concomitant standard chest radiotherapy. PATIENTS AND METHODS: Twenty-nine patients with advanced non-small-cell lung or esophageal cancer enrolled in this phase I study to evaluate escalating docetaxel doses at three schedules. Docetaxel was administered as two 21-day cycles at doses of 40, 60, and 75 mg/m2 per cycle. Docetaxel administration schedules were as follows: schedule A, once every 3 weeks; schedule B, 2 of 3 weeks; or schedule C, weekly. Six weeks of concomitant standard chest radiotherapy in 1.8- to 2.0-Gy daily fractions was delivered to 60 Gy total. RESULTS: Dose-limiting esophagitis and neutropenia were encountered with schedules A and B at docetaxel doses of 60 mg/m2 per cycle. The docetaxel MTD for schedules A and B was 40 mg/m2 per cycle. Dose-limiting esophagitis was also observed with schedule C; however, there was no neutropenia. For schedule C, we identified the MTD as 60 mg/m2 per cycle (20 mg/m2/wk). Other toxicities encountered included thrombocytopenia, hypersensitivity reaction, and pulmonary infiltrates (fatal in two patients). Late toxicity of esophageal stricture occurred in five patients. CONCLUSION: Esophagitis and neutropenia are the dose-limiting toxicities of docetaxel administered with concomitant chest radiotherapy. Weekly administration of docetaxel allows for the highest total docetaxel dose during chest radiotherapy. We identified the recommended phase II docetaxel dose as 20 mg/m2 administered weekly with concomitant chest radiotherapy for 6 weeks.

Clinical studies of docetaxel (Taxotere) and concomitant chest therapy.

The administration of concomitant chemoradiotherapy has been shown to increase local and regional control of non-small cell lung cancer. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) has single-agent activity in non-small cell lung cancer, as well as radiation-enhancing potential in preclinical studies. Therefore, its investigation with concomitant radiotherapy in the clinical setting is justified. Since the clinical interactions of docetaxel and concomitant chest radiotherapy have not been previously described, we initiated a phase I study with the goal of determining the maximum tolerated dose of docetaxel and the optimal schedule for its administration during a standard course of radiation therapy to the chest, in addition to defining the dose-limiting toxicities of this regimen. This report describes the design and preliminary results of this study.