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2.
Invest New Drugs ; 26(6): 553-9, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18626572

ABSTRACT

UNLABELLED: Docetaxel is second generation taxoid that has shown activity against a variety of cancers and has been approved for use in cancers of the breast, lung, head and neck, ovaries and prostate. Temozolomide is an alkylating agent which crosses the blood brain barrier and has demonstrated antitumor activity against a broad range of tumor types, including malignant glioma, melanoma, non small cell lung cancer and carcinoma of the ovary and colon. A Phase I trial was conducted to determine the toxicity of this combination in refractory solid tumor patients. METHODS: Twenty five patients with metastatic cancers were enrolled in a Phase I dose escalation trial. Docetaxel was administered weekly in 5 escalating doses of 25 to 35 mg/ m(2) as a one-hour bolus intravenous infusion for 3 consecutive weeks. Temozolamide was administered orally daily for 3 weeks (escalating doses of 75 to 100 mg/m(2)). Cycles were repeated at 4 week intervals. RESULTS: The maximum tolerated dose (MTD) was not determined in this study. The most commonly reported adverse events were mild to moderate nausea, vomiting and fatigue. Thrombocytopenia was the most commonly observed grade 3 and 4 hematological toxicity. Eight patients had dose interruptions for adverse events and only one patient had a dose reduction while receiving 30 mg/ m(2) of docetaxel and 90 mg/ m(2) of temozolomide due to grade 3 thrombocytopenia. Two patients achieved partial responses and 88% of the patients are deceased. The median survival is 8.4 months. CONCLUSIONS: The combination of docetaxel and temozolomide was well tolerated and these agents can be safely combined. For phase II trials, docetaxel 35 mg/ m(2) IV day 1, 8 and 15, and daily temozolomide at 100 mg/ m(2) day 1-21 are recommended.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Docetaxel , Dose-Response Relationship, Drug , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Metastasis , Survival Rate , Taxoids/administration & dosage , Temozolomide
3.
Clin Pharmacol Ther ; 81(3): 354-61, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17339865

ABSTRACT

Interferon-alpha1 (IFN-alpha1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-alpha2, the only recombinant IFN-alpha with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5-270 mug/m(2) of recombinant IFN-alpha1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 microg/m(2); 1.5 x 10(4) human antiviral units/m(2)). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-alpha1b were at 3 h; an increase of approximately eightfold in both C(max) and AUC occurred between 15 microg/m(2) and 270 microg/m(2). Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after > or =3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 microg/m(2). Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-alpha1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-alpha1 in virus infections and cancer.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Interferon-alpha/adverse effects , Interferon-alpha/pharmacokinetics , Pharmacogenetics , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Body Temperature/drug effects , Cohort Studies , Cytokines/biosynthesis , Dose-Response Relationship, Drug , Female , Gene Expression/drug effects , Humans , Interferon-alpha/therapeutic use , Male , Middle Aged , Neoplasms/drug therapy , Neopterin/biosynthesis , Survival Analysis , TNF-Related Apoptosis-Inducing Ligand/biosynthesis , Ubiquitins/biosynthesis , beta 2-Microglobulin/biosynthesis , beta 2-Microglobulin/genetics
4.
Invest New Drugs ; 20(3): 305-10, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12211213

ABSTRACT

INTRODUCTION: Recombinant human interferon-a2b (rHuIFN-alpha2b) and Interleukin-2 have limited effectiveness in the treatment of metastatic renal cell carcinoma (MRCC). Gemcitabine (Gemzar) is also reported to have activity against MRCC, and recent in vitro, in nude mice xenografts, and human data suggests increased activity of gemcitabine (Gemzar) when combined with IFN-alpha2b. PURPOSE: A phase I clinical trial utilizing gemcitabine (Gemzar and rHuIFN-alpha2b was conducted in patients with metastatic renal cell carcinoma. METHODS: Treatment consisted of: gemcitabine (Gemzar) 600 mg/m2 I.V. weekly and rHuIFN-alpha2b 1.0 MU/m2 (dose level A) or 3.0MU/m2 S.C. (dose level B) three times a week for 6 weeks with a 2 weeks rest period. RESULTS: Thirteen patients were entered into the trial and were evaluated. Dose limiting toxicity was predominantly hematologic, and was seen at dose level B. This included grade 3 anemia (1 patient), neutropenia (1 patient), and nausea (1 patient) and grade 4 neutropenia (1 patient). The maximal tolerated dose was gemcitabine (Gemzar) 600 mg/m2 I.V. weekly and rHuIFN-alpha2b 1.0 MU/m2 three times a week. CONCLUSION: This combination of gemcitabine (Gemzar) and rHuIFN-alpha2b has significant hematologic toxicity despite low doses of each agent. Further investigation of this combination using this schedule is not recommended.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Deoxycytidine/analogs & derivatives , Kidney Neoplasms/drug therapy , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/administration & dosage , Drug Resistance, Neoplasm , Female , Hematologic Diseases/chemically induced , Humans , Injections, Subcutaneous , Interferon alpha-2 , Interferon-alpha/administration & dosage , Male , Middle Aged , Recombinant Proteins , Gemcitabine
5.
Ann Oncol ; 12(5): 655-9, 2001 May.
Article in English | MEDLINE | ID: mdl-11432624

ABSTRACT

BACKGROUND: Metastatic renal-cell carcinoma is a neoplasm that is minimally responsive to cytotoxic chemotherapy. Tumor regression following therapy with cytokines such as interferon alpha and or interleukin-2 is seen in selected subsets of patients. Investigations with other immunomodulatory cytokines, such as GM-CSF and IL-6 are therefore of interest. PATIENTS AND METHODS: A phase I trial of concomitantly administered granulocyte macrophage-colony stimulating factor (3.0 mcg/kg/day s.c. d1-14) and escalating doses of interleukin-6 (1.0, 5.0 or 10.0 microg/kg/day d1-14) was conducted in patients with metastatic renal-cell carcinoma to explore the toxicity of the combination and its hematologic effects. RESULTS: The most common side effects seen were fever, fatigue and arthralgias. Dose limiting toxicity included thrombocytosis and hyperbilirubinemia in patients receiving 10 microg/kg/day of IL-6. The hematologic effects of IL-6 and GM-CSF included leukocytoses and thrombocytosis, with increases in peripheral blood progenitors (BFU-E, CFU-GM, and CFU-GEMM). Evidence of platelet activation demonstrated by increased platelet expression of CD62 was found. No clinical responses were observed. CONCLUSIONS: The combination of IL-6 and GM-CSF has pleotropic hematologic effects. Further studies with this combination for the treatment of renal-cell carcinoma are not recommended.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Interleukin-6/pharmacology , Kidney Neoplasms/drug therapy , Adult , Aged , Carcinoma, Renal Cell/pathology , Dose-Response Relationship, Drug , Female , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , Humans , Hyperbilirubinemia/chemically induced , Injections, Subcutaneous , Interleukin-6/administration & dosage , Interleukin-6/adverse effects , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Platelet Activation , Thrombocytosis/chemically induced , Treatment Outcome
6.
J Cancer Res Clin Oncol ; 127(5): 319-24, 2001 May.
Article in English | MEDLINE | ID: mdl-11355147

ABSTRACT

PURPOSE: A phase I followed by a phase II trial utilizing rIL-2, IFN alpha, and 5-FU were conducted in patients with unresectable and/or metastatic renal cell carcinoma. METHODS: Treatment consisted of: rIL-2 at 5.0 x 10(6) IU/m2 SQ on days 1-5 for 4 weeks, rHUIFN alpha-2a at 5.0 x 10(6) U/m2 SQ on days 1, 3, and 5 for 4 weeks, and 5-FU by IV bolus on days 1-5 during week 1. In the phase I study, patients were treated at varying doses of 5-FU: I-none, II-250 mg/m2, III-300, and IV 375. A phase II trial was then conducted utilizing the same schedule and maximum tolerated dose (MTD) for 5-FU. RESULTS: Twenty patients were entered into the phase I trial. Dose-limiting toxicity included grade III nausea and vomiting, and one sudden cardiac death. The MTD for 5-FU was determined to be 300 mg/m2. In the phase II trial, a median of two cycles of therapy was administered to 25 evaluable patients. Toxicity was moderate and consisted primarily of fevers, chills, fatigue, nausea/vomiting, and anorexia. Grade IV thrombocytopenia, consistent with ITP, developed in one patient each on the phase I and phase II trial. Seven partial responses were seen among 25 patients treated in the phase II trial for a 28% (CI 12-49%) response rate. CONCLUSIONS: The addition of 5-FU to rIL-2 and rHuIFN alpha-2a appears to increase the toxicity of this therapy. Randomized trials will be required to determine if efficacy is enhanced.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Carcinoma, Renal Cell/drug therapy , Fluorouracil/therapeutic use , Immunologic Factors/therapeutic use , Immunotherapy , Interferon-alpha/therapeutic use , Interleukin-2/therapeutic use , Kidney Neoplasms/drug therapy , Adult , Aged , Anorexia/chemically induced , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Carcinoma, Renal Cell/mortality , Chills/chemically induced , Combined Modality Therapy , Death, Sudden, Cardiac/etiology , Dose-Response Relationship, Drug , Fatigue/chemically induced , Female , Fever/chemically induced , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Interleukin-2/administration & dosage , Interleukin-2/adverse effects , Kidney Neoplasms/mortality , Life Tables , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Survival Analysis , Thrombocytopenia/chemically induced , Vomiting/chemically induced
7.
Cancer Chemother Pharmacol ; 48(6): 493-8, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11800031

ABSTRACT

PURPOSE: The present study was designed to determine the toxicity and maximum tolerated doses of oral intermittent oral capecitabine and subcutaneous (s.c.) rHuIFNalpha2a in patients with metastatic renal cell carcinoma (RCC). The pharmacokinetics of capecitabine and its metabolites were also investigated. METHODS: A total of 27 patients were treated at four dose levels of capecitabine (825 or 1000 mg/m2 twice daily orally, days 1-14, 22-36) and rHuIFNalpha2a (1.5 or 3.0 MU/m2 s.c. three times weekly). Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chroatography/mass spectrometry in ten patients. RESULTS: The toxicity of combined capecitabine and rHuIFNalpha2a was moderate. Patients experienced mild nausea/vomiting (70%) and diarrhea (63%). The hand-foot syndrome was seen in 67% of patients and was generally mild, as was hematologic toxicity. Dose-limiting toxicity included diarrhea, mucositis, neutropenia and the hand-foot syndrome. The dose level recommended for further trials included capecitabine 1000 mg/m2 twice daily and rHuIFNalpha2a 3.0 MU/m2 three times weekly. One patient had a partial response of a liver lesion (duration > 200 days). Pharmacokinetic parameters of capecitabine and its metabolites (5'-deoxy-5-fluorouridine, 5-fluorouracil and alpha-fluoro-beta-alanine) were similar to those reported by other authors. There was rapid conversion to 5'-deoxyuridine. The peak plasma concentrations of capecitabine occurred between 0.5 and 3.0 h. CONCLUSIONS: The combination of capecitabine and rHuIFNalpha2a was well tolerated. The recommended dose levels for phase II trials are: rHuIFNalpha2a 3.0 MU/m2 s.c. three times weekly and oral capecitabine 1000 mg/m2 twice daily for 2 weeks. No evidence of an effect of rHuIFNalpha2a on the pharmacokinetics of capecitabine or its metabolites was apparent. A phase II trial in untreated patients with metastatic RCC is planned.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Kidney Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Capecitabine , Chromatography, Liquid , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/pharmacokinetics , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Fluorouracil/analogs & derivatives , Humans , Injections, Subcutaneous , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Interferon-alpha/pharmacokinetics , Kidney Neoplasms/pathology , Male , Mass Spectrometry , Maximum Tolerated Dose , Middle Aged , Neoplasms/drug therapy , Neutropenia/chemically induced , Peripheral Nervous System Diseases/chemically induced
8.
Cancer Chemother Pharmacol ; 46(3): 251-4, 2000.
Article in English | MEDLINE | ID: mdl-11021744

ABSTRACT

PURPOSE: To perform a phase II trial of pyrazoloacridine (PZA), a novel DNA intercalator, in patients with metastatic colorectal carcinoma and no previous therapy. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over 3 h every 21 days. Pharmacokinetic studies to determine PZA plasma concentrations were performed. RESULTS: No responses were seen in 14 response-evaluable patients. Patients received a median of two cycles of PZA (range 1-6). Toxicity included neutropenia and neurologic side-effects, which were > or = grade III in 73% and 14%, respectively. High plasma concentrations of PZA (Cmax) correlated with low neutrophil counts (P = 0.04). CONCLUSIONS: PZA is inactive at this dose and schedule in colorectal cancer, and produces moderately severe toxicity.


Subject(s)
Acridines/therapeutic use , Antineoplastic Agents/therapeutic use , Colonic Neoplasms/drug therapy , Intercalating Agents/therapeutic use , Pyrazoles/therapeutic use , Rectal Neoplasms/drug therapy , Acridines/adverse effects , Acridines/pharmacokinetics , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Colonic Neoplasms/blood , Female , Humans , Intercalating Agents/adverse effects , Intercalating Agents/pharmacokinetics , Male , Middle Aged , Neoplasm Metastasis , Nervous System Diseases/chemically induced , Neutropenia/chemically induced , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Rectal Neoplasms/blood
9.
J Immunother ; 23(5): 549-56, 2000.
Article in English | MEDLINE | ID: mdl-11001548

ABSTRACT

The authors evaluated the clinical and biologic effects of human recombinant interleukin-6 (rhIL-6) in patients with refractory cancer. A phase 1 trial using escalating doses of rhIL-6 (1-50 microg x kg(-1) x d(-1), Monday through Friday for 4 weeks) was performed in 30 patients. Toxicity was moderate and the maximum tolerated dose was determined to be 25 microg x kg(-1)x d(-1) based on cardiac and neurocortical toxicity in one patient each and thrombocytosis (platelets > 800,000/microL) in three patients. One patient with non-small-cell lung cancer had a partial response after three cycles of therapy. The biologic effects of rhIL-6 included anemia and dose-related thrombocytosis. Various proinflammatory activities were induced and included dose-related cyclical increases in peripheral blood monocytes and the CD14+/CD45RB+ +/- CD16C+ mononuclear cell populations. These increases were accompanied by increased levels of C-reactive protein, serum neopterin, and type I soluble tumor necrosis factor receptor. In contrast, rhIL-6 did not affect lymphocyte numbers or function (cytotoxicity, cytokine levels, immunoglobulin levels), with the possible exception of IL-2Ralpha mRNA induction in peripheral blood lymphocytes. rhIL-6 has pleiotropic proinflammatory actions in vivo and moderate toxicity when administered as long-term therapy.


Subject(s)
Interleukin-6/administration & dosage , Neoplasms/drug therapy , Acute-Phase Reaction , Adult , Aged , Aged, 80 and over , B-Lymphocytes/drug effects , Cell Count , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Hematologic Diseases/chemically induced , Humans , Injections, Subcutaneous , Interleukin-6/adverse effects , Interleukin-6/pharmacokinetics , Male , Middle Aged , Monocytes/drug effects , Neoplasms/mortality , Neoplasms/pathology , Patient Selection , Probability , Recurrence , Statistics, Nonparametric , Survival Rate , Treatment Outcome
10.
Urology ; 54(4): 617-23; discussion 623-4, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10510917

ABSTRACT

OBJECTIVES: To determine the feasibility and toxicity of the adoptive transfer of ex vivo-activated T lymphocytes that have been sensitized to autologous tumor vaccine in vivo. METHODS: Twenty patients with extensive metastatic renal cell carcinoma received systemic adoptive immunotherapy with autologous T cells in the absence of conjunctional interleukin-2 (IL-2) administration. Patients were vaccinated intradermally with irradiated autologous tumor cells and granulocyte-macrophage colony-stimulating factor as an adjuvant to stimulate an immune response. Inguinal lymph nodes draining the vaccine site were surgically removed, and the cells were stimulated with staphylococcal enterotoxin A followed by expansion in 60 IU/mL IL-2, and in some cases additionally stimulated with anti-CD3 monoclonal antibody and IL-2, to obtain a large number of cells. RESULTS: The staphylococcal enterotoxin A/IL-2 activation induced vigorous proliferation of T cells (median expansion 26-fold) that were a mixture of CD4 and CD8 T lymphocytes. Activated cells were infused intravenously at doses ranging from 2x10(9) to 9.5x10(10). There was minimal toxicity consisting of grade 1 or 2 fever and nausea, and the entire treatment was delivered as outpatient therapy. One patient had a partial response, one had a mixed response, and 8 had stable disease lasting at least 5 months. CONCLUSIONS: Adoptive transfer of ex vivo-activated, tumor vaccine-primed lymph node cells is feasible and is associated with minimal toxicity when used alone. These results warrant further study in a Phase II trial.


Subject(s)
Carcinoma, Renal Cell/secondary , Carcinoma, Renal Cell/therapy , Immunotherapy, Adoptive , Kidney Neoplasms , T-Lymphocytes , Adult , Aged , Feasibility Studies , Female , Humans , Immunotherapy, Adoptive/adverse effects , Male , Middle Aged
11.
Clin Cancer Res ; 5(10): 2780-9, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10537342

ABSTRACT

Interleukin 12 (IL-12) is known to play an important role in the development of an antitumor response. Its activity has been shown to be dependent upon the intermediate production of IFN-gamma and the influx into the tumor of CD8 lymphocytes. In a murine model, tumor regression induced by IL-12 treatment correlated with IFN-gamma, IP-10, and Mig expression in the tumor bed and was abrogated by antibodies to both chemokines. Here we examined the effects of rHuIL-12 on IFN-gamma and CXC chemokine gene expression in patients with renal cell carcinoma (RCC) in an attempt to determine whether a similar series of molecular events leading to IL-12-mediated tumor regression in mice is also detectable in humans. As in the murine RENCA model, cultured RCC cells themselves could be induced by IFN-gamma to synthesize IP-10 and Mig mRNA. Explanted RCC produced IFN-gamma and IP-10 mRNA in response to IL-12 treatment, which was consistent with the finding that biopsied RCC tumors from IL-12-treated patients also variably expressed augmented levels of those molecules after therapy. Although Mig mRNA was present in the majority of biopsied tumors prior to treatment, both the Mig and IP-10 chemokines as well as IFN-gamma were induced in the peripheral blood mononuclear cells of IL-12-treated patients. Skin biopsies of IL-12-treated patients also all synthesized IP-10 mRNA. This study demonstrates that recombinant human IL-12 therapy of patients with RCC has the potential to induce the expression of gene products within the tumor bed that may contribute to the development of a successful antitumor response.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Chemokines, CXC/biosynthesis , Intercellular Signaling Peptides and Proteins , Interferon-gamma/biosynthesis , Interleukin-12/pharmacology , Kidney Neoplasms/drug therapy , Animals , Chemokine CXCL10 , Chemokine CXCL9 , Chemokines, CXC/genetics , Humans , Mice , RNA, Messenger/analysis , Recombinant Proteins/pharmacology , Tumor Cells, Cultured
12.
Am J Clin Oncol ; 22(3): 237-42, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10362328

ABSTRACT

Mature results are reported from a phase II trial of accelerated induction chemoradiotherapy and surgical resection for stage III non-small-cell lung cancer whose prognosis is poor. Surgically staged patients with poor prognosis stage III non-small-cell lung cancer were eligible for this study. Four-day continuous intravenous infusions of cisplatin 20 mg/m2/day, 5-fluorouracil 1,000 mg/m2/day, and etoposide 75 mg/m2/day were given concurrently with accelerated fractionation radiation therapy, 1.5 Gy twice a day, to a total dose of 27 Gy. Surgical resection followed in 4 weeks. Identical postoperative chemotherapy and concurrent radiation to a total dose of 40 to 63 Gy was subsequently given. Between February 1991 and June 1994, 42 eligible and evaluable patients, 23 with stage IIIA disease and 19 with stage IIIB disease, were entered in this trial. Treatment was well tolerated. The pathologic response rate was 40%. This response was complete in 5%. With a median follow-up of 54 months, the Kaplan-Meier 4-year survival estimate is 19%: 26% for stage IIIA and 11% for stage IIIB patients. Patients with a pathologic response, resectable disease, or pathologic downstaging to stage 0, I, or II had a better survival. The 4-year estimates of locoregional and distant disease control are 70% and 19%, respectively. It is concluded that although the ultimate role of concurrent chemoradiotherapy and surgery in stage III non-small-cell lung cancer must await the results of phase III clinical trials, survival and locoregional control in this study appear improved in comparison with historical experience. There is a subset of patients, able to undergo resection with pathologic downstaging, who have a projected survival equivalent to that of patients with more limited disease. Clinical or pathologic tools to identify these patients before treatment would be highly useful.


Subject(s)
Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Combined Modality Therapy , Humans , Lung Neoplasms/pathology , Neoplasm Staging , Pneumonectomy , Prognosis , Radiotherapy Dosage , Survival Analysis
13.
Clin Cancer Res ; 4(10): 2337-47, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9796963

ABSTRACT

Studies have demonstrated abnormalities of the CD3/T-cell antigen receptor (TCR) and pathways of signal transduction in T lymphocytes from animals and patients with advanced malignancy. Diminished expression of TCRzeta and p56(lck) that are associated with the TCR and reduced nuclear localization of RelA containing nuclear factor kappaB (NFkappaB) complexes have been noted. These defects have been described in T cells from patients with malignant melanoma, renal cell carcinoma (RCC), ovarian cancer, and colorectal cancer. Preliminary observations also indicate possible correlation with clinical variables such as stage in selected instances. To further characterize altered expression of TCRzeta, p56(lck), and impaired activation of NFkappaB, T lymphocytes were obtained from 65 patients with RCC, the majority of whom were receiving combination cytokine therapy [interleukin (IL)-2, IFN alpha-containing regimens] and 37 control individuals. In 29 of these patients, levels of TCRzeta and p56(lck) were determined by Western blots of T-cell lysates and semiquantitated using densitometry. Relative levels were then correlated with a series of clinical variables including response to therapy, performance status, survival, disease sites, age, and others. In another group of 28 patients (three individuals from the first group), the frequency of abnormal NFkappaB activation was studied using electrophoretic mobility shift assays after activation of T cells with phorbol myristate acetate/ionomycin or anti-CD3 monoclonal antibody. Changes in these signaling molecules during cytokine treatment were also investigated. TCRzeta and p56(lck) were detected in the peripheral blood T cells in 27 of 29 patients, and overall, reduced levels were noted visually in 12 of 29 (41%) and 13 of 29 (45%) individuals, respectively. When levels were semiquantitated using densitometry, significant decreases of TCRzeta (P = 0.029) and p56(lck) (P = 0.029) but not CD3epsilon (P = 0.131), compared with control levels, were found. In patients treated with IL-2/IFN alpha-based therapy, relative levels of TCRzeta increased significantly (P = 0.002) on day 15 of cycle one compared with the baseline. Correlations of TCRzeta or p56(lck) levels with response or disease variables, except for lower TCRzeta levels (P < 0.001) in the presence of bone metastases, were not found. Abnormal NFkappaB activation after stimulation with phorbol myristate acetate/ionomycin and/or anti-CD3 monoclonal antibody was found in 59% of patients (17 of 28) and was not accounted for by the advanced age of the study cohort. Activation of NFkappaB in peripheral blood T cells was inducible during cytokine therapy in four of six individuals who displayed impaired NFkappaB activity prior to therapy. Moreover, impaired activation of NFkappaB does not appear linked to a reduction of TCRzeta expression, because in five patients, normal TCRzeta levels were present although kappaB binding was not inducible. In the majority of patients with advanced RCC, peripheral blood T cells express TCRzeta and p56(lck), and in a subset, reduced levels of these TCRzeta associated molecules are seen that may increase during cytokine-based therapy. Abnormal activation of NFkappaB is also present in >50% of patients and may also revert to normal during IL-2/IFN alpha-based treatment. This alteration in NFkappaB activation occurred in the presence of normal expression of TCRzeta-associated signaling elements. The clinical significance of these findings remains unclear.


Subject(s)
Carcinoma, Renal Cell/immunology , Cytokines/therapeutic use , Kidney Neoplasms/immunology , Signal Transduction , T-Lymphocytes/metabolism , Carcinoma, Renal Cell/therapy , Humans , Kidney Neoplasms/therapy , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/analysis , Membrane Proteins/analysis , NF-kappa B/metabolism , Receptors, Antigen, T-Cell/analysis
14.
Clin Cancer Res ; 4(5): 1183-91, 1998 May.
Article in English | MEDLINE | ID: mdl-9607576

ABSTRACT

Patients with advanced renal cell carcinoma were treated in a Phase I trial with escalating doses of recombinant human interleukin-12 (rHuIL-12) given on days 1, 8, and 15 of each 28-day cycle. Treatment in the initial dose scheme consisted of a fixed dose with dose levels of 0.1, 0.5, and 1.0 microg/kg given to cohorts composed of three or six patients. On the basis of the toxicity profile, a second scheme (up-titration) was undertaken wherein rHuIL-12 was escalated for each patient from week 1 to week 2, to a target dose given week 3 and thereafter; cohort target dose levels were 0.5, 0.75, 1.0, 1.25, and 1.5 microg/kg. Fifty-one patients were treated: 32 (63%) had prior cytokine therapy and 19 (37%) had received no prior systemic therapy. The maximum tolerated dose for the fixed dose scheme was 1.0 microg/kg. Dose-limiting toxicities included increase in transaminase concentration, pulmonary toxicity, and leukopenia. The most severe toxicities occurred with the first injection and were milder upon further treatment. With the up-titration dose scheme, the maximum tolerated dose was reached at 1.5 microg/kg, and dose-limiting toxicity consisted of an increase in serum transaminase levels. At the maximum tolerated dose of 1.5 microg/kg, serum IL-12 levels increased to a mean peak level of 706 pg/ml. Serum levels of IFN-gamma increased to a mean peak level of about 200 pg/ml at 24 h after the first maintenance dose of 1.5 microg/kg. The best responses were as follows: one patient had complete response, 34 patients were stable, 14 patients showed progression, and 1 patient was inevaluable. In conclusion, rHuIL-12 was relatively well tolerated when administered by s.c. injection. The recommended dose according to the up-titration schedule of rHuIL-12 (microg/kg) for Phase II trials was as follows: cycle 1, 0.1 (day 1), 0.5 (day 8), 1.25 (day 15); cycle 2 onwards, 1.25. Phase II trials of rHuIL-12 were initiated in previously untreated patients with renal cell carcinoma and in patients with melanoma.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Interleukin-12/administration & dosage , Kidney Neoplasms/drug therapy , Adolescent , Adult , Aged , Carcinoma, Renal Cell/metabolism , Female , Humans , Injections, Subcutaneous , Interleukin-12/adverse effects , Interleukin-12/pharmacokinetics , Kidney Neoplasms/metabolism , Male , Middle Aged , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacokinetics , Treatment Outcome
15.
Urology ; 51(2): 232-6, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9495703

ABSTRACT

OBJECTIVES: To assess the effect of local, regional, and distant recurrence on pouch function in patients with locally advanced bladder cancer treated by cystectomy and continent diversion. METHODS: A review of 64 consecutive patients undergoing orthotopic (n = 40) or continent cutaneous (n = 24) urinary diversion was performed; 25 patients (39.1%) had locally advanced cancers as defined by deep muscle invasion, extension into perivesical fat, stromal invasion of the prostate, or node-positive disease. Patients were followed at 6-month intervals with physical examination, assessment of voiding function, and computed tomography (CT) scans. RESULTS: The pelvic recurrence rate was 4.7% in the overall group and 12% in patients with locally advanced disease. In the 39 patients with organ-confined tumors, 34 (87%) are alive without evidence of recurrence and have normal pouch function with a median follow-up of 27 months. Four patients in this group receiving systemic chemotherapy for clinical recurrences have retained normal pouch function until last follow-up or death. In the 25 patients with locally advanced tumors, 15 (60%) are alive without evidence of recurrence and have normal pouch function with a median follow-up of 15 months. Seven patients in this group received a median three cycles of adjuvant chemotherapy, and 4 patients received chemotherapy for clinically evident recurrences. Surgical recovery did not delay the onset of adjuvant therapy in any patient, nor did problems specifically related to the presence of a continent pouch delay any cycle of chemotherapy in those patients treated for recurrent disease in either group. Only 1 patient (1.5%) experienced treatment-related toxicity related to the presence of a continent diversion. CONCLUSIONS: This experience suggests that the use of orthotopic or continent cutaneous diversions after cystectomy in patients with locally advanced bladder cancer is safe, does not interfere with the delivery of subsequent therapy, and allows most patients to anticipate normal pouch function even in the presence of recurrent disease.


Subject(s)
Cystectomy , Neoplasm Recurrence, Local/epidemiology , Urinary Bladder Neoplasms/surgery , Urinary Reservoirs, Continent , Adult , Aged , Chemotherapy, Adjuvant , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Staging , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology
16.
Invest New Drugs ; 16(3): 255-8, 1998.
Article in English | MEDLINE | ID: mdl-10360605

ABSTRACT

Circadian administration of chemotherapy has been reported to decrease toxicity and possibly enhance efficacy. Between March 1991 and December 1993, 18 evaluable patients with progressive, hormone-refractory metastatic prostate cancer were treated in this phase II trial of circadian infusion floxuridine (FUDR). The drug was delivered through a central venous catheter using a CADD-Plus computerized pump such that approximately 70% of the drug was administered between 3 and 9 p.m. and the rest (30%) was administered between 9 p.m. and 3 p.m. The dose of FUDR was 0.15 mg/kg/day x 14 days every 4 weeks. A total of 79 complete cycles was administered. Two of 18 evaluable patients (11.1%) had decreases in PSA lasting five and eight months. No objective responses or improvement in bone scans was noted. The major toxicity observed was diarrhea. Although circadian infusion FUDR is feasible and tolerable, it has limited activity in hormone refractory prostate cancer.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Floxuridine/administration & dosage , Neoplasms, Hormone-Dependent/drug therapy , Prostatic Neoplasms/drug therapy , Antimetabolites, Antineoplastic/therapeutic use , Circadian Rhythm , Floxuridine/therapeutic use , Humans , Infusions, Intravenous , Male , Neoplasm Metastasis , Prostatic Neoplasms/pathology , Survival Analysis
17.
Cancer ; 80(6): 1134-40, 1997 Sep 15.
Article in English | MEDLINE | ID: mdl-9305715

ABSTRACT

BACKGROUND: To test the hypothesis that the cytoprotectant amifostine attenuates the thrombocytopenia produced by carboplatin, the authors performed a randomized trial comparing treatment with carboplatin alone versus the combination of amifostine and carboplatin. METHODS: Patients with refractory or carboplatin-sensitive malignancies were randomized to receive either carboplatin, 500 mg/m2 alone or carboplatin, 500 mg/m2 in conjunction with 2 doses of amifostine of 910 mg/m2 each. RESULTS: Fifty-five patients with a variety of malignancies were entered on this study. One patient withdrew from each arm prior to the administration of any therapy, leaving 30 evaluable patients treated with carboplatin alone and 23 treated with the combination of amifostine and carboplatin. For 82 cycles of therapy with amifostine plus carboplatin, the median platelet nadir was 127 x 10(9)/L while the median platelet nadir was 88 x 10(9)/L over the 80 courses of therapy with carboplatin alone (P = 0.023). The median platelet nadir after the first cycle of therapy was 144 x 10(9)/L for patients treated with amifostine plus carboplatin and 85 x 10(9)/L for patients treated with carboplatin alone (P = 0.24). The median survival for 9 patients with advanced nonsmall cell lung carcinoma treated with carboplatin alone was 39 weeks whereas the median survival for 12 such patients treated with amifostine plus carboplatin was 52 weeks (P = 0.116). CONCLUSIONS: These data support the hypothesis that amifostine attenuates the myelosuppression of carboplatin. Additional studies of amifostine in combination with carboplatin-containing chemotherapy regimens are warranted.


Subject(s)
Amifostine/therapeutic use , Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Neoplasms/drug therapy , Thrombocytopenia/prevention & control , Adult , Aged , Aged, 80 and over , Bone Marrow/drug effects , Carboplatin/adverse effects , Female , Humans , Male , Middle Aged , Neutrophils/drug effects , Platelet Count/drug effects , Thrombocytopenia/chemically induced , Treatment Outcome
18.
J Immunother ; 20(4): 301-11, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9220320

ABSTRACT

A phase II trial was conducted in patients with metastatic renal cell carcinoma, to assess the clinical efficacy and immunoregulatory effects of continuous-infusion recombinant interleukin-2 (rIL-2) (9.0 x 10(6) IU/m2/day on days 1-5, 8-12, 15-19, and 22-26) and subcutaneously administered recombinant human interferon-alpha 2b (rHuIFN alpha 2b) (10.0 x 10(6) U/m2/day TIW). Thirty-six patients with metastatic renal cell carcinoma, performance status of 0-1, and measurable disease who had not received prior rIL-2, rHuIFN alpha 2b, or chemotherapy were treated. Patients with CNS metastases, active infections, history of another malignancy within 3 years, and those requiring corticosteroids were ineligible. Cycles of rIL-2 and rHuIFN alpha 2b were administered in the outpatient department every 6-8 weeks in stable or responding patients until patient tolerance or a complete response were reached. Doses were modified for grade III or IV toxicity. Ancillary studies included three-color immunocytometric analysis of peripheral blood lymphocytes, repetitive tumor biopsies for immunohistologic analysis of infiltrating cells and proliferative responses of tumor infiltrating lymphocytes, and preliminary studies of changes in peripheral blood T-lymphocyte signal transduction molecules [T-cell receptor (TCR)-zeta, p56ick, p59fyn]. Thirty-six eligible patients were treated, with 6 of 36 patients (17%, 95% confidence interval 6-33%) responding (3 complete response, 3 partial response). In two of the partial responders, and in an additional three patients with either minimal tumor regression (one patient) or stable disease (two patients), surgical removal of residual disease was undertaken. The median survival of all patients was 14 months. The toxicity of this regimen was severe, but outpatient administration was possible in most instances. Immunoregulatory effects on T-cell subsets included increases in various CD3+ CD25+/- HLADr+/- subsets unrelated to response. Tumor biopsies before and/or during therapy were obtained in 17 patients, and no consistent alterations in the degree of T-lymphocyte or macrophage infiltrates could be detected. In a subset of patients, tumor infiltrating lymphocyte proliferative responses and levels of peripheral blood T-cell signal transduction molecules (TCR-zeta, p56lck, p59fyn) were investigated. Abnormalities were found in selected patients, which improved during rIL-2/rHuIFN alpha 2b therapy. This cytokine combination produces tumor regression in selected patients with metastatic renal cell carcinoma. Surrogate immunologic markers associated with response were not identified; however, preliminary studies demonstrate investigation of immune defects and their reversal with cytokine therapy is possible.


Subject(s)
Carcinoma, Renal Cell/therapy , Interferon-alpha/administration & dosage , Interleukin-2/administration & dosage , Kidney Neoplasms/therapy , Adult , Aged , Antigens, CD/analysis , Carcinoma, Renal Cell/immunology , Female , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Interleukin-2/adverse effects , Kidney Neoplasms/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Male , Middle Aged , Recombinant Proteins
19.
Cancer ; 77(6): 1149-53, 1996 Mar 15.
Article in English | MEDLINE | ID: mdl-8635137

ABSTRACT

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is involved in the differentiation and proliferation of various hematopoietic precursors. It also has been reported to enhance the antitumor activity of various mature effector cells. Previous reports have noted preclinical antitumor activity in a murine model utilizing genetically engineered tumor cells and instances of tumor regression in patients with solid tumors receiving GM-CSF. In the present study, a Phase II trial of human recombinant GM-CSF (GM-CSFrh) in patients with metastatic renal cell carcinoma (RCC) was conducted to investigate further the potential antitumor activity of this cytokine. METHODS: Twenty-six eligible patients with metastatic RCC received 3 microgram/kg of GM-CSFrh subcutaneously for 14 days, with cycles repeated every 28 days. RESULTS: Two of 26 patients (8%; 95% confidence interval 1-25%) demonstrated partial tumor responses during GM-CSFrh therapy. Both individuals who responded had received prior therapy. A median of three cycles per patient were administered, and toxicity was mild. CONCLUSIONS: GM-CSFrh may mediate tumor regression in patients with metastatic RCC; however, the level of activity in previously treated patients is low.


Subject(s)
Carcinoma, Renal Cell/therapy , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Kidney Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Female , Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , Humans , Injections, Subcutaneous , Male , Middle Aged , Neoplasm Metastasis , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Treatment Outcome
20.
Clin Cancer Res ; 2(2): 347-57, 1996 Feb.
Article in English | MEDLINE | ID: mdl-9816178

ABSTRACT

We conducted a Phase I trial of s.c. recombinant human interleukin 3 (rhIL-3) to evaluate the toxicity, maximal tolerated dose, pharmacokinetics, and in vivo biological effects of this cytokine. Thirty-one patients with refractory cancer were entered into the study between November 1991 and June 1993. Therapy consisted of s.c. rhIL-3 daily for 15 days administered to cohorts of three to nine patients at dose levels of 60-4000 microgram/m2/day. Cycles were repeated at intervals of 28 days. Seventy-five cycles of rhIL-3 were administered (median, two per patient) and the maximal tolerated dose was 2000 microgram/m2/day. Toxicity was moderate, with most patients developing chills, fever, and myalgia. Dose-limiting toxicity consisted of diarrhea (two patients) and headache (one patient). Hematological effects of rhIL-3 included significant dose-related increases of WBC (P < 0.001), neutrophils (P < 0.001), and eosinophils (P < 0.001). Platelet counts and absolute lymphocyte numbers also increased. Various CD3(+) lymphocyte subsets increased; however, lytic activity (natural killer and lymphokine-activated killer) of peripheral blood lymphocytes was not enhanced. Serum levels of the soluble IL-2 receptor increased in a dose-related fashion, and IL-2-induced lymphocyte proliferation also was increased variably. Pharmacokinetic studies were performed in 13 patients, and area under the curve and maximal concentration values increased with increasing rhIL-3 dose levels (P < 0.001) and correlated with maximal changes from baseline in WBC, neutrophils, and eosinophils. rhIL-3 antibodies were detected in 8% of patients by day 29 of cycle 1 but were not neutralizing. rhIL-3 is well tolerated when administered s.c. and has reproducible hematological and immunological effects. The pleiotropic effects of this cytokine on various in vivo biological parameters were demonstrated clearly. Further studies of its immunoregulatory effects are warranted.


Subject(s)
Interleukin-3/adverse effects , Neoplasms/therapy , Adult , Aged , Blood Cell Count/drug effects , Female , Humans , Injections, Subcutaneous , Interleukin-3/administration & dosage , Interleukin-3/pharmacokinetics , Interleukin-6/blood , Lymphocyte Activation/drug effects , Male , Middle Aged , Neoplasms/blood , Neoplasms/immunology , Receptors, Interleukin-2/analysis , Recombinant Proteins/adverse effects
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