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Biomedical subjects

R A Figlin

Publications and source records attributed to R A Figlin.

At least 19 recordsLinked to original sources
PubMed2007

Combined cytoreductive laser therapy and immunotherapy for palliation of metastatic renal cell carcinoma to the head and neck.

Interleukin-2 (IL-2) remains the mainstay of treatment for metastatic renal cell carcinoma (RCC), but minimally invasive surgical techniques have provided new options for the combined treatment of RCC. Two patients with metastatic RCC to the head and neck treated by combined laser-induced thermal therapy and IL-2 were described in this case report. Both patients had an extended survival compared to the historical survival of 10 months for metastatic RCC but eventually succumbed to progressive disease. The authors' initial experience with metastatic RCC suggests that laser thermoablation and immunotherapy in selected patients with metastatic RCC is warranted as a palliative treatment, but a larger study with long-term follow-up is necessary to determine the effectiveness of this approach.

Antineoplastic Agents↗
PubMed2006

Joint association of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder cancer prognosis.

The impact of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism on bladder cancer is unknown. We found no clear correlations between the FGFR4 genotype and risk of bladder cancer or pathological parameters. Neither the polymorphism nor TP53 mutation status was an independent predictor of prognosis, but they might act jointly on the disease-specific survival of patients.

Aged↗
PubMed2001

Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points. RESULTS: In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment. CONCLUSION: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.

Administration, Oral↗
PubMed2001

Improved prognostication of renal cell carcinoma using an integrated staging system.

PURPOSE: To integrate stage, grade, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) into a clinically useful tool capable of stratifying the survival of renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: The medical records of 661 patients undergoing nephrectomy at University of California Los Angeles between 1989 and 1999 were evaluated. Median age was 61 years, male-to-female ratio was 2.2:1, and median follow-up was 37 months. Survival time was the primary end point assessed. Sixty-four possible combinations of stage, grade, and ECOG PS were analyzed and collapsed into distinct groups. The internal validity of the categorized was challenged by a univariate analysis and a multivariate analysis testing for the accountability of each UCLA Integrated Staging System (UISS) category against independent variables shown to have impact on survival. RESULTS: Combining and stratifying 1997 tumor-node-metastasis stage, Fuhrman's grade and ECOG PS resulted in five survival stratification groups designated UISS, and numbered I to V. The projected 2- and 5-year survival for the UISS groups are as follows for the groups: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; and V, 9% and 0%, respectively. UISS accounted for the significant variables in the variate analysis. CONCLUSION: A novel system for staging and predicting survival for RCC integrating clinical variables is offered. UISS is simple to use and is superior to stage alone in differentiating patients' survival. Our data suggests that UISS is an important prognostic tool for counseling patients with various stages of kidney cancer. Further prospective large-scale validation with external data is awaited.

Adult↗
PubMed2001

Measuring the incremental cost of clinical cancer research.

PURPOSE: To summarize evidence on the costs of treating patients in clinical trials and to describe the Cost of Cancer Treatment Study, an ongoing effort to produce generalizable estimates of the incremental costs of government-sponsored cancer trials. METHODS: A retrospective study of costs will be conducted with 1,500 cancer patients recruited from a randomly selected sample of institutions in the United States. Patients accrued to either phase II or phase III National Cancer Institute-sponsored clinical trials during a 15-month period will be asked to participate in a study of their health care utilization (n = 750). Costs will be measured approximately 1 year after their trial enrollment from a combination of billing records, medical records, and an in-person survey questionnaire. Similar data will be collected for a comparable group of cancer patients not in trials (n = 750) to provide an estimate of the incremental cost. RESULTS: Evidence suggests insurers limit access to trials because of cost concerns. Public and private efforts are underway to change these policies, but their permanent status is unclear. Previous studies found that treatment costs in clinical trials are similar to costs of standard therapy. However, it is difficult to generalize from these studies because of the unique practice settings, insufficient sample sizes, and the exclusion of potentially important costs. CONCLUSION: Denials of coverage for treatment in a clinical trial limit patient access to trials and could impede clinical research. Preliminary estimates suggest changes to these policies would not be expensive, but these results are not generalizable. The Cost of Cancer Treatment Study is an ongoing effort to provide generalizable estimates of the incremental treatment cost of phase II and phase III cancer trials. The results should be of great interest to insurers and the research community as they consider permanent ways to finance cancer trials.

Clinical Trials as Topic↗
PubMed2001

Dendritic cell-based immunotherapy of renal cell carcinoma.

Although mostly resistant to cytotoxic therapy, renal cell carcinoma has been a testing ground for immunotherapy. The approval of interleukin-2 for the treatment of renal cell carcinoma was a landmark "proof of principle" which showed that agents working solely via the immune system can cause durable cancer remission. Dendritic cells are central to immune-mediated surveillance and destruction of abnormal cells. They possess all the components required to educate immune effector cells that can then mediate tumor destruction. In vitro strategies to expand and load dendritic cells with antigens have now led to human vaccine trials in renal cell carcinoma and other malignancies.

Carcinoma, Renal Cell↗
PubMed2001

Vaccine and gene therapy of renal cell carcinoma.

The concept of tumor vaccines is not new. However, advances in gene transfer technology, tumor immunology, molecular biology, and methods of monitoring antitumor response, have allowed for novel, more specific vaccine approaches. For example, first-generation tumor vaccines were composed of whole inactivated cancer cells, or tumor lysates (Tuly) given together with immune adjuvants like bacillus Calmette-Guerin (BCG). Current strategies include tumor cells modified with genes encoding molecules necessary to stimulate a cytotoxic T cell response, such as cytokine genes, foreign HLA genes, tumor-associated antigen (TAA) genes, and even costimulatory molecules. Activation of cellular immunity requires at least three synergistic signals including presentation of specific tumor antigens, costimulatory signals (B7 molecules), and propagation of the immune response via cytokine release. In general, tumor cells often fail to demonstrate any of these immunostimulatory properties. Dendritic cell-based vaccines are gaining popularity as these cells can properly present TAA to the immune system, thus circumventing the poor antigen-presenting qualities of tumor cells. Dendritic cells can be "loaded" with TAA or other molecules either by their natural endocytotic capabilities, or by genetic modification.

Carcinoma, Renal Cell↗
PubMed2001

Reevaluation of the 1997 TNM classification for renal cell carcinoma: T1 and T2 cutoff point at 4.5 rather than 7 cm. better correlates with clinical outcome.

PURPOSE: We analyzed the effects of the change in TNM classification from the 1987 to the 1997 version and suggest a modified tumor size cutoff point between T stages 1 and 2 for renal cell carcinoma. MATERIALS AND METHODS: We evaluated a database containing the records of 661 patients who underwent nephrectomy between 1989 and 1999. The effect of the change in TNM classification on the distribution of patients between stages, the rates of M+ and N+ disease, and the local and distant recurrence rates were outlined for 280 patients with T stages 1 and 2 disease. The Cox model was used to identify the optimal cutoff point between T1 and T2 disease, and the resulting effect of adopting this cutoff was outlined. RESULTS: A total of 174 and 128 cases were down staged from 1987 version stage T2 to 1997 version stage T1 and from 1987 TNM stage II to 1997 TNM stage I, respectively. Survival was not significantly different in patients with 1997 TNM stages I and II disease due to a lack of survival difference during the first 2 years of followup. Stage shift also caused an increase in average tumor size, the proportion of patients with high grade cancer, and M+ and N+ disease at diagnosis in 1997 stages T1 and T2 as well as an increase in the proportion of 1997 stage T2N0M0 cases at diagnosis with systemic failure. Analysis of 11 potential cutoff points between 1 and 10 cm. revealed that 4.5 cm. was most predictive of patients survival (hazards ratio 4.99, p = 0.0001). Using this cutoff resulted in improved discriminatory power of the TNM classification and a moderating effect on the distribution of patients, average tumor size, high grade disease, M+ and N+ disease at diagnosis, and systemic failure between T(14.5) and T(24.5) compared with 1997 T1 and T2. CONCLUSIONS: Our data imply that the current cutoff point of 7 cm. between stages T1 and T2 tumors is too high. Lowering the cutoff to 4.5 cm. resulted in better discriminatory power of the TNM classification in our dataset. This observation should be further validated by external data.

Adult↗
PubMed2000

Infusional interleukin-2 and 5-fluorouracil with subcutaneous interferon-alpha for the treatment of patients with advanced renal cell carcinoma: a southwest oncology group Phase II study.

BACKGROUND: A Phase II trial was conducted to determine the response rate of patients with advanced renal cell carcinoma to a three-drug combination of 5-fluorouracil (5-FU), interleukin-2 (IL-2), and interferon-alpha-2b (IFN-alpha). METHODS: A 2-stage accrual plan was used that was designed to determine whether response to this regimen was consistent with a true response rate of >/= 30%. The regimen was comprised of 5 treatment days weekly for 4 weeks every 6 weeks. Each weekly treatment was comprised of 5-FU, 1750 mg/m(2), continuous intravenous (i.v.) infusion over 24 hours followed by IL-2, 6 MIU/m(2)/day, continuous i.v. infusion for 4 days. IFN-alpha, 6 MU/m(2), was given subcutaneously on Days 1, 2, and 5. RESULTS: Thirty-eight patients were entered on study, 3 of whom were ineligible. Among the 35 eligible patients there were 3 confirmed partial responses (PR) and 1 complete response (CR), for an overall response rate of 11% (95% confidence interval, 3-27%). One patient considered as having a PR had minimal evidence of residual disease and was free from disease progression at > 2.5 years of follow-up, as was the patient with CR. Three additional patients not qualified as having a PR were showing signs of response at the time they were removed from protocol, and another patient who was removed from protocol early for management of an infection subsequently responded to the same regimen off protocol. Thirteen patients were considered nonassessable (NASS) for response, many of whom had multiple poor risk features and were unable to complete 1 cycle of treatment. CONCLUSIONS: This multicenter study failed to confirm an advantageous overall response rate for this three-drug regimen. However, there were two durable responses and indications of responsiveness not scored as PRs among patients with more favorable risk factor patterns, and many poor risk NASS patients. For these reasons, the response rate reported in the current study may be a conservative reflection of the effectiveness of this regimen.

Adult↗
PubMed2000

Granulocyte macrophage colony-stimulating factor and interleukin 4 enhance the number and antigen-presenting activity of circulating CD14+ and CD83+ cells in cancer patients.

Antigen-presenting cells (APCs) are essential for stimulating antigen-specific immunity, including immunity against tumor cells. We hypothesized that systemic administration of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, which promote monocytes to differentiate into dendritic cells in vitro, might enhance the number and antigen-presenting activity of CD14+ cells in vivo. Patients with metastatic solid malignancies were treated with daily s.c. injections of either GM-CSF alone (2.5 microg/kg/day) or GM-CSF in combination with IL-4 (0.5-6.0 microg/kg/day) in a multicohort study. When given alone, GM-CSF increased the number of CD14+ cells but did not enhance the cells' expression of APC markers or antigen-presenting activity. In contrast, combination therapy with GM-CSF and IL-4 stimulated CD14+ cells to acquire several APC characteristics including increased expression of HLA-DR and CD11c, decreased CD14, increased endocytotic activity, and the ability to stimulate T cells in a mixed leukocyte reaction. Combination therapy also induced a dose-dependent increase in the number of CD14-/CD83+ cells with APC activity. Clinically significant and sustained tumor regression was observed in one patient. Systemic therapy with GM-CSF and IL-4 may provide a mechanism for increasing the number and function of APCs in patients with cancer.

Antigen-Presenting Cells↗
PubMed2000

Intratumoral interleukin 2 for renal-cell carcinoma by direct gene transfer of a plasmid DNA/DMRIE/DOPE lipid complex.

Metastatic renal-cell carcinoma (RCC) is not responsive to conventional cytotoxic chemotherapy, but a subset of patients achieve a durable remission with the use of interleukin-2 (IL-2). IL-2 is currently the only Food and Drug Administration (FDA)-approved treatment for metastatic RCC, and it benefits 10-20% of those who receive it. However, it is accompanied by significant, occasionally life-threatening toxicity. Attempts to maintain the efficacy of IL-2 while minimizing systemic side effects have led to the development of IL-2 gene therapies. Leuvectin is a plasmid DNA/lipid complex composed of a plasmid DNA expression vector (VCL-1102, 30) encoding human IL-2 complexed in a 5:1 mass ratio with DMRIE/DOPE lipid (1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl ammonium bromide/dioleoylphosphatidyl ethanolamine), which has been developed for the treatment of malignancy. DMRIE/DOPE is a cationic lipid that has been shown to facilitate in vitro transfection of plasmid DNA. It has been demonstrated that in vitro transfection with the IL-2 plasmid DNA/DMRIE/DOPE complex results in the expression of sustained levels of biologically active IL-2. Established human tumor cell lines and primary human tumor cells obtained from biopsies are readily transfected in vitro, resulting in the expression of IL-2. Following in vitro transfection, IL-2 expression has been found to persist for up to several weeks in primary tumor cells. In preclinical efficacy studies in a murine model of renal-cell carcinoma the direct intratumoral administration of an IL-2 plasmid DNA/DMRIE/DOPE complex resulted in complete tumor regression in the majority of mice. In preclinical animal-safety studies, repeated administration of Leuvectin was safe and well tolerated. Following these promising preclinical trials, Leuvectin has been taken into clinical trial. The results of two early studies indicate that Leuvectin is safe, is free of systemic toxicity, and has biologic activity.

Aged↗
PubMed2000

Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria.

PURPOSE: We determine independent prognostic indicators for renal cell carcinoma using the revised 1997 TNM staging criteria. MATERIALS AND METHODS: The records of 643 consecutive patients undergoing partial or radical nephrectomy at our institution between 1987 and 1998 were reviewed. Preoperative evaluation of functional status using the Eastern Cooperative Oncology Group (ECOG) criteria was performed in all cases. Renal cell carcinoma grade and stage were evaluated using the 1997 American Joint Committee on Cancer grading and TNM staging criteria, respectively. Patients were followed for a mean plus or minus standard deviation of 47+/-40 months (median 87). Kaplan-Meier survival curves were used to determine 5-year cancer specific survival for all patient groups. Univariate analysis using log rank sum tests was performed to evaluate the prognostic significance of overall TNM stage, tumor stage, disease grade and ECOG status. Multivariate analysis was performed to determine which factors had an independent impact on survival of patients with renal cell carcinoma. RESULTS: The 5-year cancer specific survival rate was 91%, 74%, 67% and 32% for TNM stages I, II, III and IV lesions, respectively (p<0.001). Analysis demonstrated a survival rate of 83% for stage T1, 57% for stage T2, 42% for stage T3 and 28% for stage T4 disease (p<0.001), and 89% for grade 1, 65% for grade 2, and 46% for grades 3 and 4 (p<0.001). Multivariate analysis revealed that overall TNM stage and grade of disease were the most important prognostic indicators for renal cell carcinoma (p<0.001). ECOG classification was a less significant predictor (p = 0.031) and tumor stage was not shown to have any independent impact on patient survival (p = 0.138). CONCLUSIONS: Better survival rates of patients with localized and advanced renal cell carcinoma can be demonstrated with recent advances in diagnosis and treatment. The revised 1997 TNM criteria manifest an appropriate adjustment in staging renal cell carcinoma based on these improvements, with overall stage correlating with cancer specific survival. In contrast, while effectively predicting survival, tumor stage did not demonstrate an independent impact on renal cell carcinoma prognosis under multivariate analysis. Instead, other factors, such as ECOG status and more importantly grade of disease, appeared to affect survival significantly as independent elements. Based on our recent experience with patients treated for renal cell carcinoma in the era of enhanced technology and improved survival, tumor grade and molecular markers may serve as useful adjuncts to TNM staging in guiding treatment and predicting survival outcomes.

Adult↗
PubMed2000

Expanding the indications for surgery and adjuvant interleukin-2-based immunotherapy in patients with advanced renal cell carcinoma.

PURPOSE: To determine the role of surgery and adjuvant interleukin (IL)-2-based immunotherapy in the treatment of patients with advanced metastatic renal cell carcinoma PATIENTS AND METHODS: The survival of 354 consecutive patients with metastatic renal cell carcinoma treated with IL-2-based immunotherapy through the UCLA Medical Center Kidney Cancer Program was analyzed There were five groups of patients. Patients who initially presented with metastatic disease received either (1) IL-2 therapy with primary tumor in place; (2) nephrectomy followed by IL-2 therapy, or (3) nephrectomy followed by immunotherapy with IL-2 plus tumor-infiltrating lymphocytes. Patients who underwent nephrectomy for localized disease were divided into two groups: (4) those who developed metastatic disease > or = 6 months after nephrectomy and then received IL-2 therapy; and (5) those who developed metastatic disease < 6 months after nephrectomy and then received IL-2 therapy. Kaplan-Meier survival curves were generated for all patient groups. RESULTS: Among patients who received IL-2-based immunotherapy with their primary tumor in place (group 1; n = 36), 1- and 2-year survival rates were 29% and 4%, respectively, compared with 1- and 2-year survival rates of 67% and 44%, respectively, for all similar patients who underwent nephrectomy prior to IL-2 therapy (n = 235). Among patients initially presenting with metastatic disease who underwent nephrectomy followed by IL-2 therapy without tumor-infiltrating lymphocytes (group 2; n = 69), the 1- and 2-year survival rates were 53% and 25%, respectively. The best survival was observed in patients treated with nephrectomy followed by IL-2 plus tumor-infiltrating lymphocyte therapy (group 3; n = 102), which yielded 1- and 2-year survival rates of 73% and 55%, respectively. Among patients initially undergoing nephrectomy for localized disease, patients receiving IL-2-based therapy for subsequent metastasis > or = 6 months following nephrectomy (group 4; n = 128) had 1- and 2-year survival rates of 64% and 40%, respectively, compared with 45% and 15%, respectively, for patients developing metastasis < 6 months after nephrectomy (group 5; n = 19). CONCLUSION: The role of surgery prior to IL-2-based immunotherapy remains controversial Our data demonstrate that aggressive surgery is safe, causing minimal morbidity despite extensive tumor involvement, and significantly improves survival outcomes in patients with metastatic renal cell carcinoma when carried out in conjunction with an IL2-based immunotherapy regimen.

Carcinoma, Renal Cell↗
PubMed2000

Adoptive cellular therapy.

We provide a current review of adoptive cellular therapy in the management of metastatic renal cell carcinoma. A comprehensive literature review of peer-reviewed articles on the development and use of adoptive cellular immunotherapy was performed. Renal cell carcinoma is a highly immunogenic tumor that has proven resistant to standard cytotoxic chemotherapy, but has shown reproducible response to immune-based therapy. In an effort to improve responses, a variety of adoptive cellular strategies have been devised and tested in the setting of metastatic disease. Among the techniques developed, the use of lymphokine-activated killer (LAK) cells, autolymphocyte therapy (ALT), and tumor-infiltrating lymphocytes (TIL) have been the best studied. While further trials are ongoing, thus far, these approaches have not consistently shown benefit in comparison to standard immune-based treatment with biologic response modifiers, most importantly, high-dose bolus interleukin-2 (IL-2). Future approaches, including the use of dendritic cells (DC) to facilitate the development of tumor vaccines, are encouraging. Advanced renal cell carcinoma continues to inspire research of promising new cellular immunotherapeutics. The experience with LAK, ALT, and TIL has greatly increased our understanding of tumor immunobiology, and has led to the ongoing development of new technology, including DC, vaccine, and antibody therapy.

Adjuvants, Immunologic↗
PubMed1999

Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

Rituximab, an anti-CD20 antibody, has been recently approved for the treatment of low-grade or follicular non-Hodgkin's lymphoma (NHL). Because of its relatively benign side effect profile, it has been considered a nontoxic alternative to chemotherapy. Recently, however, tumor lysis syndrome (TLS) resulting from rituximab has been reported in a patient with chronic lymphocytic leukemia (CLL). We herein present two cases of rituximab-induced TLS. The first case occurred in a patient with high-grade NHL, while the second case occurred in a patient with CLL. We also present a summary of the literature regarding TLS induced by immunotherapies.

Adult↗