ABSTRACT
PURPOSE: Diagnosis and treatment of breast cancer have changed profoundly over the past 25 years. The outcome improved dramatically and was well quantified for early stage breast cancer (EBC). However, progress in the treatment of metastatic disease has been less convincingly demonstrated. We have studied survival data of patients with metastatic breast cancer (MBC) from a large academic cancer center over a period of 20 years. METHODS: Data from 1033 consecutive MBC patients who were treated at the Department of Medical Oncology of the West German Cancer Center from January 1990 to December 2009 were retrospectively analyzed for overall survival (OS) and risk factors. Patients were grouped in 5-year cohorts, and survival parameters of each cohort were compared before and after adjustment for risk factors. RESULTS: Overall survival of patients with MBC treated at specialized center has significantly improved from 1990 to 2010 (hazard ratio 0.7, 95%CI 0.58-0.84). The increments in OS have become less profound over time (median OS 1990-1994: 24.2 months, 1995-1999: 29.6 months, 2000-2004: 36.5 months, 2005-2009: 37.8 months). CONCLUSION: Survival of patients with MBC has improved between 1990 and 2004, but less from 2005 to 2009. Either this suggests an unnoticed shift in the patient population, or a lesser impact of therapeutic innovations introduced in the most recent period.
Subject(s)
Breast Neoplasms/pathology , Cancer Care Facilities , Neoplasm Metastasis , Survival Analysis , Breast Neoplasms/therapy , Female , Germany , HumansABSTRACT
BACKGROUND: Induction chemoradiotherapy plus surgery remains an option to study in IIIA(N2) and selected IIIB NSCLC. Here we report ten-year long-term survival of a prospective multicenter German-French phase-II trial with trimodality. PATIENTS AND METHODS: Mediastinoscopically proven IIIA(N2)/selected IIIB NSCLC received three cycles cisplatin (50 mg/m(2) day 1+8) and paclitaxel (175 mg/m(2)d1) qd 22. Concurrent CTx/RTx followed: 45 Gy (1.5 Gy bid) with cisplatin 50 mg/m(2) day 2+9 and etoposide 100 mg/m(2) d 4-6. Surgery was planned three to five weeks after RTx. If evaluated inoperable/irresectable at the end of RTx, definitive RTx-boost (20 Gy; 2 Gy qd) followed. Here we report 10-year-LTS for this cohort. RESULTS: All 64 patients were accrued 3/99 to 2/02. Patients characteristics: IIIA(N2)/IIIB 25/39; m/f 48/16; adeno/squamous/large-cell/adenosquamous/NOS 15/26/18/3/2; age: median 52.5 (range 33-69). 36 operated: R0 32/36 (89%); pCR 16/36 (44%). 10-year-LTS%; all 26.0; IIIA(N2) 37.1; IIIB 17.9; relevant prognostic factors (exploratory): pretreatment - histopathology (squamous/adeno) - age (<50/≥50) - Charlson-CI: 1/>1 - BMI (≥25/<25) - pack years smoking (≥10/<10); treatment-dependent - R0/no-R0. CONCLUSIONS: This regimen achieves substantial LTS. Interestingly, adenocarcinomas, older patients, unfavorable comorbidity scores, higher BMI and light smokers demonstrate poor long-term outcome even with aggressive trimodality. This dataset defines the rationale for our ongoing randomized trial with surgery after induction therapy in IIIA(N2)/selected IIIB (ESPATÜ).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Adult , Aged , Carcinoma, Non-Small-Cell Lung/mortality , Chemoradiotherapy , Cisplatin/administration & dosage , Etoposide/administration & dosage , Female , Follow-Up Studies , Humans , Induction Chemotherapy , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Male , Middle Aged , Paclitaxel/administration & dosage , Prospective Studies , Survivors , Treatment OutcomeABSTRACT
ImmunoRNases represent a highly attractive alternative to conventional immunotoxins for cancer therapy. Quantitative production of immunoRNases in appropriate expression systems, however, remains a major challenge for further clinical development of these novel compounds. Here we describe a method for high-level production and purification of a fully functional immunoRNase fusion protein from supernatants of stably transfected mammalian cells.
Subject(s)
Molecular Biology/methods , Multiple Myeloma/pathology , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/immunology , Ribonuclease, Pancreatic/biosynthesis , Ribonuclease, Pancreatic/immunology , Transfection , Animals , Cell Death/drug effects , Cell Line, Tumor , Clone Cells , Drug Screening Assays, Antitumor , Flow Cytometry , Genetic Vectors/genetics , Humans , Immunoglobulin Variable Region/immunology , Mice , Recombinant Fusion Proteins/pharmacology , Ribonuclease, Pancreatic/pharmacology , Sialic Acid Binding Ig-like Lectin 2/immunologyABSTRACT
Because of the variable clinical course of multiple myeloma, the identification of prognostic parameters is of clinical interest. Therefore, we analyzed the clinical significance of serum levels of soluble human leukocyte antigen class I molecules (sHLA-I), carboxy-terminal telopeptide of type-I collagen (ICTP), and receptor activator of nuclear factor kappa B ligand (RANKL). Compared with controls, sHLA-I were threefold (p < 0.001) elevated in multiple myeloma. Increased levels of ICTP and RANKL were demonstrated in 50 and 43% of patients, respectively. sHLA-I correlated significantly with stage of disease. Serial determination of sHLA-I in 11 patients revealed significantly higher sHLA-I levels (median [range] mug/l) during active disease than during remission (700 [250-2090] versus 380 [130-920]). ICTP demonstrated an association with stages of disease and the presence of osteolytic lesions, whereas there were no differences with respect to active/remittent disease. Importantly, levels of sHLA-I > or = 1000 microg/l and ICTP > or = 5 microg/l were significantly associated with a poor overall survival. For RANKL, no significant associations were observed with disease stages, disease status, osteolytic lesions, and survival. In conclusion, sHLA-I and ICTP serum levels seem to be of prognostic significance in multiple myeloma and might be helpful to identify patients of poor prognosis.
Subject(s)
Biomarkers, Tumor , HLA Antigens/blood , Multiple Myeloma/blood , Multiple Myeloma/pathology , Peptide Fragments/blood , Procollagen/blood , RANK Ligand/blood , Adult , Aged , Aged, 80 and over , Collagen Type I , Female , Humans , Male , Middle Aged , Multiple Myeloma/mortality , Neoplasm Staging , Peptides , Prognosis , Survival AnalysisABSTRACT
INTRODUCTION: Advanced stage/metastatic soft tissue sarcoma (STS) has a poor prognosis especially after failure of the established first-line treatment. In patients with relapsed leiomyosarcoma, however, the combination of gemcitabine (G) and docetaxel (D) recently has emerged as a valuable salvage therapy. PATIENTS AND METHODS: A retrospective analysis of G (900 mg/m2, days 1+8) and D (100 mg/m2, day 8) was performed in 34 patients with STS, and response rate (RR), overall survival (OS), time to progression (TTP), and toxicities were evaluated. RESULTS: Analysis of these 34 patients revealed a RR of 15% with no complete remission (CR) and 5 partial remissions (PR). Of note, 4/5 PR were achieved in patients with leiomyosarcoma. In 13 patients (38%) disease stabilization (SD) could be achieved resulting in a clinical benefit rate (CBR), defined as CR+PR+SD, of 53%. Median OS was 12.5 and TTP was 2.4 months for the whole group and 2.8 months for patients with leiomyosarcoma. A progression- free rate at 3 months of 38% and 45%, respectively, was observed in these 2 groups. Major side effects were 47% hematological and 26% grade 3/4 nonhematological toxicity. CONCLUSION: With regard to the observed CBR further use of GD seems to be warranted even in pretreated patients with STS.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Sarcoma/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Disease Progression , Docetaxel , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Leiomyosarcoma/drug therapy , Leiomyosarcoma/mortality , Leiomyosarcoma/pathology , Male , Middle Aged , Neoplasm Staging , Palliative Care , Retrospective Studies , Sarcoma/mortality , Sarcoma/pathology , Survival Analysis , Taxoids/administration & dosage , Taxoids/adverse effects , Uterine Neoplasms/drug therapy , Uterine Neoplasms/mortality , Uterine Neoplasms/pathology , GemcitabineABSTRACT
AIMS AND BACKGROUND: To improve the survival of patients with aggressive non-Hodgkin's lymphoma, we evaluated a risk-adapted therapeutic approach using high-dose (HD) or conventional-dose (CD) chemotherapy (CT) for poor-risk and good-risk patients, respectively. METHODS: Twenty patients were treated in each group. In both groups, the first chemotherapy cycle consisted of dexamethasone, vincristine, ifosfamide, and etoposide. Thereafter, the CD or HD patients received 3 or 2 cycles of dexamethasone, vincristine, epirubicin, and cyclophosphamide, respectively, followed by 1 cycle of dexamethasone, carboplatin, and etoposide. In the HD group cyclophosphamide, epirubicin, carboplatin, and etoposide were dose-escalated by a factor of 6, 3, 3, and 3, respectively, as compared to the CD group, and autologous peripheral blood stem cells were administered after each HD-CT cycle. RESULTS: Grade III-IV toxicities were neutropenia and thrombocytopenia (100%), anemia (55%), and stomatitis (30%) in patients with HD-CT, and neutropenia (90%) in patients with CD-CT. One toxic death occurred in a patient with HD-CT. The overall response rate was 100% in HD-CT patients, including 70% complete remissions, and 80% in CD-CT patients, including 60% complete remissions. The 10-year overall survival was 55% for patients with HD-CT and 80% for patients with CD-CT. CONCLUSIONS: The risk-adapted treatment approach showed tolerable toxicities and was associated with encouraging results.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/therapy , Neoplasm Recurrence, Local/therapy , Peripheral Blood Stem Cell Transplantation , Adolescent , Adult , Aged , Carboplatin/administration & dosage , Combined Modality Therapy , Dexamethasone/administration & dosage , Etoposide/administration & dosage , Feasibility Studies , Female , Humans , Ifosfamide/administration & dosage , Male , Middle Aged , Remission Induction , Survival Rate , Transplantation, Autologous , Vincristine/administration & dosageABSTRACT
We here describe a novel xenograft model of chronic lymphocytic leukemia (CLL) generated by infusion of human primary CLL cells into immunodeficient nonobese/severe combined immunodeficient (NOD/SCID) mice. Combined i.v. and i.p. injection of peripheral blood mononuclear cells (PBMC) from 39 patients with CLL resulted in highly reproducible splenic (37 of 39) and peritoneal (35 of 39) engraftment, which remained stable over a time span of 4 to 8 weeks. By comparison, recovery of leukemic cells from bone marrow (21 of 39) or peripheral blood (8 of 22) was substantially lower. The engraftment pattern of CLL PBMC 4 weeks posttransplant was correlated with clinical disease activity: infusion of PBMC from donors with Binet stage A, lymphocyte doubling time of >12 months, and normal lactate dehydrogenase (LDH) serum levels led to marked engraftment of T cells whereas comparably few tumor cells could be detected. In contrast, NOD/SCID mice receiving PBMC from donors with advanced stage Binet C, lymphocyte doubling time of <12 months, and elevated LDH serum levels exhibited predominant engraftment of tumor cells and comparably low numbers of T cells. These results suggest that this model reflects the heterogeneity and important clinical characteristics of the disease, and thus may serve as a tool for preclinical drug testing and investigation of the pathophysiology of CLL.
Subject(s)
Disease Models, Animal , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Adult , Aged , Aged, 80 and over , Animals , Cell Growth Processes/physiology , Female , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Middle Aged , Neoplasm Transplantation , Reproducibility of Results , Risk Factors , Spleen/pathology , T-Lymphocytes/pathology , Transplantation, HeterologousABSTRACT
The present study evaluated cellular and humoral immune parameters in myeloma patients, focusing on the effect of treatment and the risk of opportunistic infections. Peripheral blood lymphocyte subsets and serum levels of nonmyeloma immunoglobulins (Ig) were analysed in 480 blood samples from 77 myeloma patients. Untreated myeloma patients exhibited significantly reduced CD4+/45RO+, CD19+, CD3+/HLA-DR+, and natural killer (NK) cells, as well as nonmyeloma IgA, IgG and IgM. Conventional-dose chemotherapy resulted in significantly reduced CD4+ and even further decline of CD4+/CD45RO+ and CD19+ cells, most notably in relapsed patients. Additional thalidomide treatment had no significant effects on these parameters. Following high-dose chemotherapy (HD-CTX), prolonged immunosuppression was observed. Although CD8+, NK, CD19+ and CD+/CD45RO+ cells recovered to normal values within 60, 90, 360 and 720 days, respectively, CD4+ counts remained reduced even thereafter. Nine opportunistic infections were observed, including five cytomegalovirus (CMV) diseases, one Pneumocystis carinii pneumonia (PCP) and three varicella zoster virus infections with CMV diseases and PCP occurring exclusively after HD-CTX. Opportunistic infections were correlated with severely reduced CD4+, as well as CD4+/CD45RO+ and CD19+ counts. Thus, myeloma patients display cellular and humoral immunodeficiencies, which increase following conventional as well as HD-CTX, and constitute an important predisposing factor for opportunistic infections.
Subject(s)
Antibody Formation , Immunity, Cellular , Immunoglobulin Isotypes/blood , Lymphocyte Subsets/pathology , Multiple Myeloma/immunology , Opportunistic Infections/etiology , Aged , Antigens, CD/analysis , Antigens, CD19 , Antineoplastic Agents/pharmacology , CD4-Positive T-Lymphocytes , Cells, Cultured , HLA-DR Antigens/analysis , Humans , Lymphocyte Subsets/drug effects , Middle Aged , Multiple Myeloma/complications , Multiple Myeloma/pathologyABSTRACT
Hematopoietic stem cell gene transfer of the drug-resistance gene cytidine deaminase (CDD) protecting cells from the cytotoxic cytidine analogs cytarabine and gemcitabine was investigated in a murine transplant model. Following transplantation of CDD-transduced cells and cytarabine application (500 mg/kg; days 1-4; intraperitoneally) significant myeloprotection was demonstrated with nadir counts of peripheral blood granulocytes and thrombocytes of 2.9 +/- 0.6/nL versus 0.7 +/- 0.1/nL (P < .001) and 509 +/- 147/nL versus 80 +/- 9/nL (P = .008), respectively (CDD versus control). Protection also was observed from otherwise lethal gemcitabine treatment (250 mg/kg; days 1-3). Stable levels of gene-marked cells in primary and secondary recipients were demonstrated for up to 9 months, and whereas CDD overexpression clearly reduced B- and T-lymphocyte numbers, no major toxicity was observed in the myeloid compartment. Despite the profound myeloprotective properties, however, CDD overexpression did not allow for pharmacologic enrichment of transduced hematopoiesis in our model. Thus, in summary, our data establish CDD as a drug-resistance gene highly suitable for myeloprotective purposes, which, given the lack of selection observed in our hands, might best be used in combination with selectable drug-resistance genes such as MGMT (P140K) or MDR1.
Subject(s)
Bone Marrow Transplantation/immunology , Cytarabine/toxicity , Cytidine Deaminase/genetics , Deoxycytidine/analogs & derivatives , 3T3 Cells , Animals , Bone Marrow Transplantation/mortality , Colony-Forming Units Assay , Cytidine Deaminase/metabolism , Deoxycytidine/toxicity , Gene Transfer Techniques , Graft Survival/physiology , Leukocyte Count , Mice , Models, Animal , Platelet Count , Recombinant Fusion Proteins/metabolism , GemcitabineSubject(s)
Antineoplastic Agents/therapeutic use , Deoxycytidine/analogs & derivatives , Peritoneal Neoplasms/drug therapy , Pseudomyxoma Peritonei/drug therapy , Aged , Cystadenocarcinoma, Mucinous/diagnosis , Cystadenocarcinoma, Mucinous/drug therapy , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Humans , Male , Peritoneal Neoplasms/diagnosis , Pseudomyxoma Peritonei/diagnosis , GemcitabineABSTRACT
Patients undergoing resection of hepatic metastases of colorectal cancer have a high risk of extrahepatic recurrence, most likely caused by early tumor cell dissemination or the manipulation of liver tumors during surgical resection. Using immunocytochemistry, we studied 47 patients for cytokeratin (CK)-positive (+) cells in: a) bone marrow (BM) samples to determine whether tumor cell dissemination had already occurred before surgery; and b) blood samples directly taken from the hepatic vein before and during surgery of liver metastases. In addition, normal and malignant liver tissues were evaluated for markers known to be involved in tumor progression and metastasis [urokinase plasminogen activator (uPA), Her-2/neu, epidermal growth factor receptor (EGF-R)] using sandwich enzyme immunoassays. CK+ cells were detected in the BM of 26/47 patients (55%), in blood samples of 14/47 patients (30%) before surgery and 11/47 patients (23%) during surgery with a median detection rate of 1 (range, 1-14) CK+ cell per 4x10(6) MNC. No CK+ cells were found in 15/47 patients (32%) in any sample studied. Tumor tissue was obtained from 32/47 patients and normal liver tissue from 24/32 patients. While no differences were found for EGF-R and Her-2/neu, a 9-fold higher expression of uPA could be demonstrated in tumor tissue of 20/32 patients (63%) compared to normal liver tissue. When all obtained results were correlated with clinical outcome, neither the detection of CK+ cells nor the expression pattern in the tumor tissue, or the combination of both, was predictive for extrahepatic recurrence or overall survival after a mean observation time of 43 months (range, 26-54 months). Although uPa is overexpressed in liver metastases of colorectal cancer, and dissemination of CK+ cells during surgery of these metastases is a frequent event in colon cancer, these findings do not predict extrahepatic recurrence. Further characterization of single cells, especially those spread during surgery, will help to identify those patients with an increased risk of later relapse.
Subject(s)
Adenocarcinoma/pathology , Colonic Neoplasms/pathology , Digestive System Surgical Procedures/adverse effects , Liver Neoplasms/secondary , Neoplasm Recurrence, Local/etiology , Neoplasm Seeding , Adult , Aged , Aged, 80 and over , Bone Marrow Cells/metabolism , Enzyme-Linked Immunosorbent Assay , ErbB Receptors/metabolism , Female , Humans , Immunohistochemistry , Liver Neoplasms/metabolism , Liver Neoplasms/surgery , Male , Middle Aged , Receptor, ErbB-2/metabolism , Urokinase-Type Plasminogen Activator/metabolismABSTRACT
PURPOSE: Retrospective studies have shown that immunoassays measuring free light chains (FLC) in serum are useful for diagnosis and monitoring of multiple myeloma. This study prospectively evaluates the use of FLC assays and, for the first time, investigates the relationship between serum FLC concentrations and the presence and detectability of Bence Jones (BJ) proteins in the urine. PATIENTS AND METHODS: Three hundred seventy-eight paired samples of serum and urine were tested from 82 patients during the course of their disease. The sensitivities of serum FLC analysis and urine immunofixation electrophoresis (IFE) in detecting monoclonal FLC were compared. Serum FLC concentrations required for producing BJ proteins detected by IFE were determined. RESULTS: Abnormal FLC were present in 54% of serum samples compared with 25% by urine tests. In abnormal serum samples for kappa or lambda, the sensitivity of IFE to detect the respective BJ proteins in urine were 51% and 35% and the median serum FLC concentrations required to produce detectable BJ proteins were 113 and 278 mg/L. Renal excretions of monoclonal FLC increased with serum concentrations, but excretions significantly decreased at high serum concentrations combined with renal dysfunction. CONCLUSION: Serum FLC assays are significantly more sensitive for detecting monoclonal FLC than urine IFE analysis. They also have the advantage of FLC quantification and are more reliable for monitoring disease course and response to treatment.
Subject(s)
Bence Jones Protein/urine , Immunoassay/methods , Immunoelectrophoresis/methods , Immunoglobulin Light Chains/blood , Multiple Myeloma/diagnosis , Humans , Sensitivity and SpecificitySubject(s)
Clinical Trials, Phase II as Topic , Medical Oncology/standards , Randomized Controlled Trials as Topic , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Neoplasm Metastasis , Neoplasms/drug therapy , Neoplasms/pathology , Prognosis , Quality of Health Care , Salvage Therapy , Survival AnalysisABSTRACT
Epidermal growth factor receptor (EGFR) overactivity plays a significant role in colon cancer biology and has been associated with poor clinical prognosis. Early clinical trials reported efficacy of receptor-targeted compounds, including modulation of clinical irinotecan resistance. We investigated the effects of the EGFR tyrosine kinase inhibitor gefitinib on cellular determinants of irinotecan resistance in human colon cancer cells. At non-cytotoxic concentrations, gefitinib sensitized colon cancer cells to SN-38, the active metabolite of irinotecan. Gefitinib increased the SN-38-mediated induction of protein-linked DNA single-strand breaks in a dose-dependent manner, with no alteration of topoisomerase (Topo) I protein expression or enzymatic activity. Whereas Topo IIbeta protein expression was not affected by gefitinib, significant time- and concentration-dependent downregulation of Topo IIalpha protein and inhibition of its enzymatic function were observed, corresponding to a G1 phase cell cycle arrest. Gefitinib significantly inhibited EGFR-associated signaling molecules, including phospho-mitogen-activated protein kinase or protein kinase C, which may account for decreases in proliferation or topoisomerase activity, respectively. Although a dose-dependent decrease of the BCRP/MXR/ABCP half-transporter was observed under gefitinib, cellular pharmacokinetics revealed no significant differences in accumulation or retention of the active SN-38 lactone using reverse-phase HPLC analysis. This study delineates mechanisms that may contribute to the synergism observed between irinotecan and EGFR inhibitors.
Subject(s)
Antineoplastic Agents/pharmacology , Camptothecin/analogs & derivatives , Colonic Neoplasms/enzymology , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , Antineoplastic Agents/pharmacokinetics , Camptothecin/pharmacokinetics , Camptothecin/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Colonic Neoplasms/metabolism , Cyclin E/metabolism , DNA Topoisomerases, Type II/genetics , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Down-Regulation , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/metabolism , Gefitinib , Humans , Irinotecan , Phosphorylation , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin. PATIENTS AND METHODS: Twenty-seven patients with refractory solid tumors were enrolled in the initial dose-escalation part (cohorts 1, 2A, and 2B) and 10 additional patients with oxaliplatin-refractory colorectal cancer were subsequently enrolled in an extension part (cohort 3). Oxaliplatin 130 mg/m2 was given on day 1 of a 3-week cycle and oral sorafenib was administered continuously from day 4 of cycle 1 at 200 mg twice daily (cohort 1) or 400 mg twice daily (cohorts 2A, 2B, and 3). RESULTS: Adverse events were generally mild to moderate and the maximum tolerated dose was not reached. Common adverse events were diarrhea (52% of patients in the dose-escalation part and 20% in the extension part), sensory neuropathy (44% and 20%), and dermatologic toxicities (41% and 80%). No pharmacokinetic interaction between sorafenib and oxaliplatin was detectable. Two patients with gastric cancer had a partial response. Forty-three percent of patients in cohorts 1 and 2A/B and 78% of patients in cohort 3 exhibited stable disease for >or=10 weeks. CONCLUSION: Continuous oral sorafenib 400 mg twice daily was safely combined with oxaliplatin without detectable drug interactions and showed preliminary antitumor activity in this phase I study. This dose is recommended for phase II studies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Benzenesulfonates/administration & dosage , Colorectal Neoplasms/pathology , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Niacinamide/analogs & derivatives , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Phenylurea Compounds , Pyridines/administration & dosage , SorafenibABSTRACT
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Long-term survival of patients with metastatic disease has only been observed in patients with completely resected disease. Recently, the tyrosine kinase inhibitor imatinib has been found to yield responses in the majority of patients with metastatic GIST suggesting improved resectability in responding patients. Combined treatment approaches including resective surgery after imatinib treatment in patients with advanced metastatic disease have rarely been explored. We report a series of 90 patients with metastatic GIST in whom treatment with imatinib enabled 12 patients with mostly recurrent and extensive disease to be considered for resection of residual disease. In 11 of these patients, complete resection could be achieved. Viable tumor cells were found in all but one resected specimens suggesting that despite favorable radiological or clinical responses, imatinib is unlikely to induce pathological complete responses. Until more mature data from prospective trials are available, these data suggest that an early aggressive surgical approach should be considered for all patients with metastatic GIST. Further trials investigating a combined surgical and pre/postoperative treatment with imatinib in patients with advanced metastatic GIST are warranted.
Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Stromal Tumors/drug therapy , Neoplasm, Residual/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Aged, 80 and over , Benzamides , Female , Follow-Up Studies , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Stromal Tumors/surgery , Humans , Imatinib Mesylate , Male , Middle Aged , Neoplasm Metastasis , Survival Analysis , Time FactorsABSTRACT
We report on the generation of a dimeric immunoenzyme capable of simultaneously delivering two ribonuclease (RNase) effector domains on one molecule to CD22(+) tumor cells. As targeting moiety a diabody derived from the previously humanized scFv SGIII with grafted specificity of the murine anti-CD22 mAb RFB4 was constructed. Further engineering the interface of this construct (V(L)36(Leu-->Tyr)) resulted in a highly robust bivalent molecule that retained the same high affinity as the murine mAb RFB4 (K(D)=0.2 nM). A dimeric immunoenzyme comprising this diabody and Rana pipiens liver ribonuclease I (rapLRI) was generated, expressed as soluble protein in bacteria, and purified to homogeneity. The dimeric fusion protein killed several CD22(+) tumor cell lines with high efficacy (IC(50)=3-20 nM) and exhibited 9- to 48-fold stronger cytotoxicity than a monovalent rapLRI-scFv counterpart. Our results demonstrate that engineering of dimeric antibody-ribonuclease fusion proteins can markedly enhance their biological efficacy.
Subject(s)
Antibodies, Monoclonal/immunology , Antigens, CD/immunology , Antigens, Differentiation, B-Lymphocyte/immunology , Cell Adhesion Molecules/immunology , Cytotoxicity, Immunologic , Lectins/immunology , Neoplasms/immunology , Neoplasms/pathology , Recombinant Fusion Proteins/metabolism , Ribonucleases/metabolism , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/isolation & purification , Antibody Specificity , Antigens, CD/metabolism , Antigens, Differentiation, B-Lymphocyte/metabolism , Cell Adhesion Molecules/metabolism , Cell Death , Cell Line, Tumor , Cell Survival , Dimerization , Humans , Immunoglobulin Variable Region/chemistry , Immunoglobulin Variable Region/genetics , Immunoglobulin Variable Region/immunology , Inhibitory Concentration 50 , Lectins/metabolism , Mice , Protein Structure, Quaternary , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/isolation & purification , Ribonucleases/chemistry , Ribonucleases/genetics , Ribonucleases/isolation & purification , Sensitivity and Specificity , Sialic Acid Binding Ig-like Lectin 2ABSTRACT
PURPOSE: Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer. The value of adding surgery to chemotherapy and radiotherapy is unknown. PATIENTS AND METHODS: Patients with locally advanced squamous cell carcinoma (SCC) of the esophagus were randomly allocated to either induction chemotherapy followed by chemoradiotherapy (40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery (arm B). Primary outcome was overall survival time. RESULTS: The median observation time was 6 years. The analysis of 172 eligible, randomized patients (86 patients per arm) showed overall survival to be equivalent between the two treatment groups (log-rank test for equivalence, P < .05). Local progression-free survival was better in the surgery group (2-year progression-free survival, 64.3%; 95% CI, 52.1% to 76.5%) than in the chemoradiotherapy group (2-year progression-free survival, 40.7%; 95% CI, 28.9% to 52.5%; hazard ratio [HR] for arm B v arm A, 2.1; 95% CI, 1.3 to 3.5; P = .003). Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group (12.8% v 3.5%, respectively; P = .03). Cox regression analysis revealed clinical tumor response to induction chemotherapy to be the single independent prognostic factor for overall survival (HR, 0.30; 95% CI, 0.19 to 0.47; P < .0001). CONCLUSION: Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC. Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/radiotherapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Squamous Cell/surgery , Cisplatin/administration & dosage , Combined Modality Therapy , Esophageal Neoplasms/surgery , Etoposide/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Neoadjuvant Therapy , Survival AnalysisABSTRACT
While vaccination with antigen-pulsed dendritic cells (DCs) represents a promising therapeutic strategy in multiple myeloma (MM), clinical benefit, so far, has been limited to individual patients. To identify potential problems with this approach, we have analyzed the influence of treatment parameters, in particular high-dose chemotherapy (HD-CTX) and thalidomide, on in vitro DC generation and peripheral blood lymphocyte subsets in MM patients. From a total of 25 MM patients, including 14 patients on thalidomide treatment and 11 after HD-CTX, in vitro DC generation from peripheral blood monocytes under serum-free condition was investigated. In addition, peripheral blood lymphocyte subsets were assessed in 17 patients including 10 patients on thalidomide treatment and 9 patients after HD-CTX. Efficient in vitro generation of DCs (median 7.1x10(6)/100 ml peripheral blood; range 0.1-42.5x10(6)/100 ml peripheral blood) expressing DC-typical surface markers was observed in 23 MM patients (92%), although reduced expression of CD1a, CD40, CD83, and HLA-DR was observed in patients treated with thalidomide. With respect to lymphocyte subsets, MM patients showed significantly (p<0.05) reduced B and CD4+ lymphocytes in the peripheral blood. This effect was most prominent within 6 months of HD-CTX and in patients receiving thalidomide (usually in combination with CTX). CD8+ lymphocytes were significantly increased in MM patients. Thus, despite the well-known deficiencies in their immune system, adequate numbers of DCs can be generated in most myeloma patients. In patients treated with thalidomide, however, it remains to be seen whether the reduced expression of co-stimulatory molecules has functional relevance.