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Biomedical subjects

J H Schiller

Publications and source records attributed to J H Schiller.

At least 19 recordsLinked to original sources
PubMed2005

Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.

PURPOSE: Gemcitabine-platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally. DESIGN: Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes. RESULTS: A significant reduction in overall mortality in favor of gemcitabine-platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84-0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine-platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine-platinum regimens, HR 0.84 (CI: 0.71-0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93 (CI: 0.86-1.01). There was a significant decrease in the risk of disease progression in favor of gemcitabine-platinum regimens, HR 0.88 (CI: 0.82-0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine-platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine-platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77-0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82-0.96).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

The influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer.

This study evaluates the influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer (NSCLC). The Eastern Cooperative Oncology Group conducted a randomized prospective trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC. A laboratory correlative study assessed the prevalence and prognostic significance of p53 and K-ras mutations. Patients were randomized to receive either radiotherapy (RT) alone or four cycles of cisplatin and VP-16 administered concurrently with radiotherapy (CRT). Median survival was 35 months for the 285 men and 41 months for the 203 women enrolled in the study (P = 0.12). The relative risk (RR) of death for men vs women was 1.19 (95% confidence interval [CI], 0.95-1.49). Median survival of the 147 men and 95 women randomized to the RT arm was 39 months each (P = 0.35). Median survival of the 138 men and 108 women randomized to the CRT arm was 30 and 42 months, respectively (P = 0.18). Disease recurrence patterns were similar between the genders. Univariate and multivariate analyses demonstrated improved survival for women with tumors of non-squamous histology (P < 0.01). The distribution of p53 and K-ras mutations was similar between the genders and had no influence on survival. Gender does not influence survival following adjuvant RT or CRT administered to patients with completely resected stages II and IIIa NSCLC. However, women with non-squamous histology have increased survival when compared to men.

Adult↗
PubMed2001

Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group.

PURPOSE: To determine the efficacy of topotecan in combination with standard chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer (SCLC), the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial. PATIENTS AND METHODS: Eligible patients had measurable or assessable disease and an ECOG performance status of 0 to 2; stable brain metastases were allowed. All patients received four cycles of cisplatin and etoposide every 3 weeks (step 1; PE). Patients with stable or responding disease were then randomized to observation or four cycles of topotecan (1.5 mg/m(2)/d for 5 days, every 3 weeks; step 2). A total of 402 eligible patients were registered to step 1, and 223 eligible patients were registered to step 2 (observation, n = 111; topotecan, n = 112). RESULTS: Complete and partial response rates to induction PE were 3% and 32%, respectively. A 7% response rate was observed with topotecan (complete response, 2%; partial response, 5%). The median survival time for all 402 eligible patients was 9.6 months. Progression-free survival (PFS) from date of randomization on step 2 was significantly better with topotecan compared with observation (3.6 months v 2.3 months; P <.001). However, overall survival from date of randomization on step 2 was not significantly different between the observation and topotecan arms (8.9 months v 9.3 months; P =.43). Grade 4 neutropenia and thrombocytopenia occurred in 50% and 3%, respectively, of PE patients in step 1 and 60% and 13% of topotecan patients in step 2. Grade 4/5 infection was observed in 4.6% of PE patients and 1.8% of topotecan patients. Grade 3/4 anemia developed in 22% of patients who received topotecan. No difference in quality of life between topotecan and observation was observed at any assessment time or for any of the subscale scores. CONCLUSION: Four cycles of PE induction therapy followed by four cycles of topotecan improved PFS but failed to improve overall survival or quality of life in extensive-stage SCLC. Four cycles of standard PE remains an appropriate first-line treatment for extensive-stage SCLC patients with good performance status.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Central venous device-related infection and thrombosis in patients treated with moderate dose continuous-infusion interleukin-2.

BACKGROUND: This study was performed to determine the incidence of central venous device-related blood stream infection and thrombosis in patients treated with moderate dose continuous-infusion interleukin-2 (IL-2). METHODS: The records of 160 consecutive patients treated at the University of Wisconsin Hospital and Clinics, between June 1990 and June 1997, with moderate dose continuous-infusion IL-2 (IL-2 [1.5-3.0 x 10(6) U/m(2)/day] Hoffman-LaRoche, Nutley, NJ or IL-2 [4.5 x 10(6) U/m(2)/day] Chiron Corporation, Berkley, CA) were reviewed retrospectively. The majority of patients had metastatic melanoma (78 patients) or renal cell carcinoma (70 patients). All of the patients had a surgically implanted central venous device placed before starting IL-2 therapy; 89% of these were cuffed Hickman catheters. Eighty-four patients received 1 mg of warfarin per day as prophylaxis against device-related thrombosis; none received periinsertion prophylactic antibiotics. RESULTS: Twenty-one patients (13%) developed central venous device-related bloodstream infection (DRBSI) during the study period, a rate of 2 DRBSI per 1000 device-days. DRBSIs were associated with the type of immunotherapy given with IL-2 (P = 0.01) and with thrombosis (odds ratio, 4.1; 95% confidence interval, 1.5-11.4; P = 0.008) but not with patient gender, type of cancer, duration of the central device, or site of device placement. Twenty-six patients (16%) developed central venous device-related thrombosis (DRT) during immunotherapy. Low dose warfarin did not appear to prevent thrombosis. Device-related thrombosis was associated with DRBSI but not with patient gender, type of cancer, type of device, duration or location of device, or concomitant immunotherapy. CONCLUSIONS: Central venous DRBSI and DRT are significant complications that can occur during moderate dose continuous-infusion IL-2 therapy. The risk of DRBSI appears lower than the risk reported with high dose IL-2 therapy by previous investigators. The risk of DRT appears to be higher than the risk reported for patients with similar devices but not given IL-2. Low dose warfarin did not prevent DRT when started after device placement.

Adult↗
PubMed2001

Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: a Laboratory Ancillary Study on an Eastern Cooperative Oncology Group Prospective Randomized Trial of Postoperative Adjuvant Therapy.

PURPOSE: To determine the prognostic and predictive significance of p53 and K-ras mutations in patients with completely resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized preoperatively to receive adjuvant postoperative radiotherapy (Arm A) or radiotherapy plus concurrent chemotherapy (Arm B). p53 protein expression was studied by immunohistochemistry (IHC) and p53 mutations in exons 5 to 8 were evaluated by single-strand conformational analysis. K-ras mutations in codons 12, 13, and 61 were determined using engineered restriction fragment length polymorphisms. RESULTS: Four hundred eighty-eight patients were entered onto E3590; 197 tumors were assessable for analysis. Neither presence nor absence of p53 mutations, p53 protein expression, or K-ras mutations correlated with survival or progression-free survival. There was a trend toward improved survival for patients with wildtype K-ras (median, 42 months) compared with survival of patients with mutant K-ras who were randomized to chemotherapy plus radiotherapy (median, 25 months; P = .09). Multivariate analysis revealed only age and tumor stage to be significant prognostic factors, although there was a trend bordering on statistical significance for K-ras (P = .066). Analysis of survival difference by p53 by single-stranded conformational polymorphism and IHC, interaction of p53 and K-ras, interaction of p53 and treatment arm, nodal station, extent of surgery, weight loss, and histology did not reach statistical significance. CONCLUSION: p53 mutations and protein overexpression are not significant prognostic or predictive factors in resected stage II or IIIA NSCLC. K-ras mutations may be a weak prognostic marker. p53 or K-ras should not be routinely used in the clinical management of these patients.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Phase I/II trial of docetaxel and vinorelbine in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy.

We conducted a phase I/II trial of the combination of docetaxel and weekly vinorelbine in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) who were refractory or resistant to platinum-based regimens. The objectives of the study were (1) to determine the maximum tolerated doses of docetaxel and weekly vinorelbine when given in combination and (2) to evaluate the response to and quantitative and qualitative toxicity of this combination of agents. Patients were required to have an ECOG performance status of 0 or 1, evaluable lesions, and no prior treatment with docetaxel or vinorelbine. A total of 30 patients were treated on this phase I/II study. Eight patients were treated at various doses on the phase I portion of the study. Twenty-two patients (11 males, 11 females, median age 64.5 years) were treated at the phase II dose of vinorelbine 15 mg/m(2) weekly with docetaxel 60 mg/m(2) on day 1 of a 21 day cycle. Twenty of these 22 patients enrolled at the phase II dose required dose modification or delay. Sixteen patients experienced absolute neutrophil count (ANC) <500/mm(3), and eight patients had neutropenic fever. Four patients experienced partial response (18%), nine patients had stable disease (41%), and nine patients had progressive disease (41%). With a median follow-up of 11 months, median survival for these 22 patients was 15.9 months (95% CI 8.1, 23.6 months). Median time to disease progression was 3.2 months with a 95% CI of (1.4, 4.1) months. Thus, the combination of docetaxel 60 mg/m(2) every 3 weeks and vinorelbine 15 mg/m(2) weekly appears to be active as a second line regimen in NSCLC, although it is a highly myelosuppressive regimen requiring dose modification in 91% of patients.

Adult↗
PubMed2001

Current standards of care in small-cell and non-small-cell lung cancer.

Lung cancer is the leading cause of cancer-related death in the United States, accounting for over 30% of cancer deaths in men and 25% in women. Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are uniformly aggressive tumors, with rates of regional or distant metastases at diagnosis as high as 70%. Because the majority of these tumors are unresectable, patients with relatively good performance status receive platinum-based chemotherapy. Although no treatment consensus exists, currently recommended regimens for SCLC include PE (cisplatin and etoposide), CAV (cyclophosphamide, doxorubicin, and vincristine), CAE (cyclophosphamide, doxorubicin, and etoposide), and CAVE (cyclophosphamide, doxorubicin, vincristine, and etoposide). Of these, the PE regimen has been widely accepted in the United States, although CE (carboplatin and etoposide) provides better tolerability. For NSCLC, standard chemotherapy regimens have included platinum-based therapy (cisplatin and a vinca alkaloid or PE). Data from recent studies suggest that the addition of paclitaxel to platinum modestly improves tumor response and survival in NSCLC. Although SCLC and NSCLC are both responsive to first-line chemotherapy, most patients relapse and die from their disease, with 5-year survival rates of approximately 15%. Given the disappointing survival rates associated with SCLC and NSCLC, the introduction of new cytotoxic agents has been eagerly anticipated. Evidence of improved response and extended survival is mounting for various combinations of established regimens (e.g., PE) with newer drugs exhibiting novel mechanisms of action and single-agent antitumor activity, such as gemcitabine, paclitaxel, docetaxel, vinorelbine, and topotecan. This article reviews the current standards of care in SCLC and NSCLC, and introduces the potential role of newer agents given in combination with standard chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Future role of topotecan in the treatment of lung cancer.

Topotecan (HYCAMTIN; GlaxoSmithKline, Brentford, Middlesex, UK) is a novel topoisomerase I inhibitor with potentially broad applicability in the treatment of solid and hematologic malignancies. In addition to its use in relapsed small-cell lung cancer (SCLC), topotecan is under investigation in numerous studies for first-line therapy in SCLC and for first- and second-line treatment of non-small-cell lung cancer (NSCLC). Preliminary evidence presented in this supplement demonstrates that single-agent topotecan and topotecan-based combination regimens are active in these settings. In addition to its potential use in SCLC and NSCLC, the feasibility and antitumor activity of topotecan as single-agent therapy and in combination therapy are under active investigation in a variety of other solid and hematologic tumors. Other important avenues of investigation include the feasibility and tumor activity of a more convenient oral formulation, as well as the investigation of alternate regimens (e.g., 3-day, weekly), with high priority given to regimen toxicity, patient convenience, and quality of life. Preliminary results of some of these trials are presented in this summary. The results of other clinical experience trials are eagerly anticipated.

Administration, Oral↗
PubMed2000

Long forms of the dopamine receptor (DRD4) gene VNTR are more prevalent in substance abusers: no interaction with functional alleles of the catechol-o-methyltransferase (COMT) gene.

Substance abuse is a complex behavior that is caused by both environmental and genetic factors. Work to understand the genetic factors has focused on genes related to dopamine activity because of its critical role in rewarding and reinforcing behaviors. The DRD3 and other dopamine receptor subtypes are expressed in many areas of the limbic system, and have been the objects of study for their possible roles in several neuropsychiatric disorders. Interest in variants of the D4 gene was heightened by reports that some alleles were more frequent in individuals who score high on Novelty Seeking, an aspect of personality that may be related to drug seeking behavior. We now show that the long form of the DRD4 gene is more frequent in individuals with high quantity/frequency of drug use compared to controls (chi(2) = 5.7, df = 1, P = 0.017, odds ratio = 1.89, CI = 1.1-3.2). There is no difference in DRD3 allele frequencies in these samples, and there is no interaction of DRD4 alleles with those of the catecholamine-o-methyl- transferase gene (COMT) that we previously identified to be more frequent in substance abusers than controls [Vandenbergh, et al.: 1997: Am. J. Med. Gen. 74:439-442].

Alleles↗
PubMed2000

A phase Ib/II trial of granulocyte-macrophage-colony stimulating factor and interleukin-2 for renal cell carcinoma patients with pulmonary metastases: a case of fatal central nervous system thrombosis.

BACKGROUND: Interleukin-2 (IL-2) and granulocyte-macrophage-colony stimulating factor (GM-CSF) are cytokines with nonoverlapping pleiotropic effects. In a prior Phase Ib study, this combination of agents exhibited antitumor effects in the lungs of four of eight patients with renal cell carcinoma and pulmonary metastases. We conducted this Phase Ib/II trial to determine the response rate of renal cell carcinoma patients with pulmonary metastases treated with continuous infusion IL-2 plus GM-CSF. METHODS: Patients with renal cell carcinoma and pulmonary metastases were treated with 1.5, 2.25, or 4.5 x 10(6) IU/m(2)/day 96-hour continuous infusion IL-2 on Days 1-4, 8-11, and 15-18, and 1.25, 2.25, or 2.5 microg/kg/day GM-CSF on Days 8-19. RESULTS: Sixteen patients were treated per protocol, 14 of whom could be evaluated for disease progression. None of these 14 patients had >50% shrinkage of either total tumor burden or pulmonary metastasis. One patient developed Grade 5 neurotoxicity. Autopsy revealed acute multifocal cerebral venous thrombosis as well as acute subdural and subarachnoid hemorrhage. CONCLUSIONS: The combination of IL-2 and GM-CSF may be associated with marked morbidity and, as in one case in this study, mortality. No significant antitumor activity was appreciated. Thus, the combination of IL-2 and GM-CSF, when administered at this dose and according to this schedule, does not appear to be active in renal cell carcinoma and is associated with significant toxicities. Further studies using this combination of agents should only be undertaken with extreme caution and particular attention to neurotoxicity.

Adult↗
PubMed2000

Pilot and safety trial of carboplatin, paclitaxel, and thalidomide in advanced non small-cell lung cancer.

We performed a pilot study to assess the safety of thalidomide in combination with standard chemo-therapy in patients with advanced non small-cell lung cancer. Patients with unresectable stage IIIA, IIIB, or IV disease were enrolled starting in July 1999. Patients received paclitaxel 225 mg/m2 over 3 hours and carboplatin area under the curve = 6.0 with thalidomide at a starting daily dose of 200 mg. The thalidomide dose was escalated, if tolerated, by 200 mg per week to a target dose of 1000 mg per day and could continue for up to 6 months. Patients with stages IIIA and IIIB disease without effusion received radiotherapy with concurrent thalidomide after 2 cycles of chemotherapy. Nine patients were enrolled: one with IIIA disease, three with IIIB disease, and five with stage IV disease. Five of nine patients had previously been treated with chemotherapy and/or radiotherapy. The most frequent side effects noted were fatigue, myalgia, constipation, neuropathy, and myelosuppression. Sixteen of the 17 (94%) episodes of grade 3 or 4 hematologic toxicity occurred in the five patients who had previously received chemotherapy, although no patients developed neutropenic fever. The median tolerated daily thalidomide dose was 600 mg. One patient with IIIA disease had a partial response after 2 cycles of chemotherapy and went on to receive radiotherapy with thalidomide. One patient with stage IV disease continues on this study with stable disease at 187 days. The median time to progression was 118 days. This preliminary data supports the further investigation of this combination in chemotherapy-naive patients with advanced non small-cell lung cancer.

Journal Article↗
PubMed2000

A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer.

Raf proteins play a central role in the mitogen-activated protein kinase signaling pathway and hence are involved in oncogenic transformation and tumor cell proliferation. ISIS 5132 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically down-regulates c-raf expression. We report here an initial study of the safety and tolerability of an i.v. infusion of ISIS 5132 in patients with advanced cancer. A continuous i.v. infusion of ISIS 5132 was administered for 21 days every 4 weeks to 34 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 5132 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 5.0 mg/kg body weight was reached. Toxicity was scored by common toxicity criteria, and tumor response was monitored. Pharmacokinetic studies were performed for 30 patients treated at doses of < or =4.0 mg/kg/day. The initial dose of ISIS 5132 was 0.5 mg/kg body weight and was successfully increased incrementally to 5.0 mg/kg body weight. Toxicities through the 4.0 mg/kg dose level were not dose limiting. Side effects were minimal and could not be specifically related to ISIS 5132. Two patients had prolonged stabilization of their disease, and one patient with ovarian carcinoma had a significant response with a 97% reduction in CA-125 levels. ISIS 5132, an antisense oligonucleotide against c-raf, was well tolerated at doses up to and including 4.0 mg/kg/day by 21-day continuous i.v. infusion and demonstrated antitumor activity at the doses tested.

Adult↗
PubMed1999

A randomized Phase II study of interleukin-2 with and without beta-interferon for patients with advanced non-small cell lung cancer: an Eastern Cooperative Oncology Group study (PZ586).

Interleukin-2 (IL-2) and beta-interferon (beta-IFN) are biologic agents with antitumor activity observed in preclinical models. Some studies of patients with advanced non-small cell lung cancer treated with IL-2 report relatively long survival, despite low response rates. Seventy-six evaluable patients with stage IV non-small cell lung cancer were treated in a randomized Phase II study with either IL-2 alone or IL-2 plus beta-IFN. Patients received either IL-2 at 6 x 10(6) Cetus units/m2 3 days weekly or the combination of IL-2 at 5 x 10(6) Cetus units/m2 plus beta-IFN at 6 x 10(6) units/m2, both given 3 days weekly. Both biologic agents were administered by intravenous bolus injection on an outpatient basis. Objective responses were observed in 3/76 (4%)) patients. Grade 4 toxicity occurred in 3/39 patients treated with IL-2 alone, and in 4/37 patients treated with IL-2 plus beta-IFN. An additional lethal respiratory toxicity occurred in a patient who received IL-2 plus beta-IFN. The median survival of all patients treated on this study was 33 weeks. Despite producing only a 4% objective response rate. IL-2 appears to have a favorable impact on survival comparable to chemotherapy. The role for this immune therapy in the management of non-small cell lung cancer requires further study.

Adenocarcinoma↗
PubMed1999

Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.

Antineoplastic Agents↗
PubMed1999

Warfarin-5-FU interaction--a consecutive case series.

Five patients from a single institution received concomitant warfarin and 5-fluorouracil (5-FU) during a 3-year period. The mean weekly warfarin dose before starting chemotherapy was 40.66 mg and during chemotherapy it was 24 mg (p=0.0026). All patients required a warfarin dosage reduction (range 18-74%, mean 44%). Two patients were hospitalized, one with a major retroperitoneal bleed, the other for fresh-frozen plasma administration and observation. Maximum international normalized ratios (INRs) ranged from 3.66-23.7. This series confirms a common, clinically significant interaction between warfarin and 5-FU. An interaction between capecitabine, the orally available prodrug of 5-FU, and warfarin also has been reported. We recommend weekly monitoring of prothrombin time and INR for all patients receiving concomitant warfarin and 5-FU or capecitabine.

Anticoagulants↗
PubMed1999

Distinct clinical and laboratory activity of two recombinant interleukin-2 preparations.

Interleukin-2 (IL-2) is a potent lymphokine that activates natural killer cells, T cells, and other cells of the immune system. Several distinct recombinant human IL-2 preparations have shown antitumor activity, particularly for renal cell cancer and melanoma. Somewhat distinct immune and clinical effects have been noted when different IL-2 preparations have been tested clinically; however, the regimens and doses used were not identical. To compare these more directly, we have evaluated two clinical recombinant IL-2 preparations in vitro and in vivo using similar regimens and similar IUs of IL-2. We used the Food and Drug Administration-approved, commercially available Chiron IL-2 and the Hoffmann LaRoche (HLR) IL-2 supplied by the National Cancer Institute. Using equivalent IUs of IL-2, we noted quantitative differences in vitro and in vivo in the IL-2 activity of these two preparations. In patients receiving comparable IUs of the two preparations, HLR IL-2 induced the release of more soluble IL-2 receptor alpha into the serum than Chiron IL-2. In addition, more toxicities were noted in patients receiving 1.5 x 10(6) IU of HLR IL-2 than were seen in patients treated with 1.5 x 10(6) or even 4.5 x 10(6) IU of Chiron IL-2. These toxicities included fever, nausea and vomiting, and hepatic toxicity. In vitro proliferative assays using IL-2-dependent human and murine cell lines indicated that the IU of HLR IL-2 was more effective than Chiron IL-2 at inducing tritiated thymidine incorporation. Using flow cytometry, we also found quantitative differences in the ability of these two preparations to bind to IL-2 receptors. These findings indicate that approximately 3-6 IU of Chiron IL-2 are required to induce the same biological effect as 1 IU of HLR IL-2.

Animals↗
PubMed1999

Future directions in non-small cell lung cancer.

Although chemotherapeutic regimens remain limited in activity against non-small cell lung cancer, some novel cytotoxic agents and radiotherapy techniques, alone or in combination, have shown promising advances. Numerous clinical trials have demonstrated increases in overall response rates, and some agents have shown additive or synergistic effects against tumor tissue. The cytoprotectant amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) is being assessed for its protection of normal tissue against the toxic effects of chemotherapy and radiotherapy and for its potential role in enhancing the efficacy of these modalities. Protection from dose-limiting toxicities may allow dose escalation and improve the therapeutic index. Current and future investigations of novel agents and modalities, with or without cytoprotectants, should lead to better prognosis and prolonged survival rates.

Amifostine↗