Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 75
Filter
1.
Leukemia ; 27(12): 2351-6, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23670297

ABSTRACT

Several cytogenetic abnormalities are associated with poor outcomes in multiple myeloma (MM). We prospectively analyzed the impact of cytogenetic abnormalities on outcomes during the phase 2 PX-171-003-A1 study of single-agent carfilzomib for relapsed and refractory MM. In the response-evaluable population (257/266), fluorescence in situ hybridization (FISH)/conventional cytogenetic profiles were available for 229 patients; 62 (27.1%) had high-risk cytogenetics--del 17p13, t(4;14) or t(14;16) by interphase FISH or deletion 13 or hypodiploidy by metaphase cytogenetics--and 167 (72.9%) had standard-risk profiles. Generally, baseline characteristics were similar between the subgroups, but International Staging System stage III disease was more common in high- vs standard-risk patients (41.9% vs 27.5%) as was Eastern Cooperative Oncology Group performance status 1/2 (85.5% vs 68.3%). Overall response was comparable between the subgroups (25.8% vs 24.6%, respectively; P=0.85), while time-to-event end points showed a trend of shorter duration in high-risk patients, including median duration of response (5.6 months (95% confidence interval (CI) 3.7-7.8) vs 8.3 months (95% CI 5.6-12.3)) and overall survival (9.3 (95% CI 6.5-13.0) vs 19.0 months (95% CI 15.4-NE); P=0.0003). Taken together, these findings demonstrate that single-agent carfilzomib is efficacious and has the potential to at least partially overcome the impact of high-risk cytogenetics in heavily pre-treated patients with MM.


Subject(s)
Antineoplastic Agents/therapeutic use , Chromosome Aberrations , Multiple Myeloma/drug therapy , Oligopeptides/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Multiple Myeloma/genetics , Survival Analysis , Treatment Outcome
2.
Leukemia ; 27(5): 1139-45, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23183426

ABSTRACT

The probability of survival is conventionally calculated from autologous hematopoietic cell transplantation (aHCT). Conditional survival takes into account the changing probability of survival with time survived, but this is not known for aHCT populations. We determined disease- and cause-specific conditional survival for 2388 patients treated with aHCT over a period of 20 years at a single institution. A total of 1054 deaths (44% of the cohort) were observed: 78% attributed to recurrent disease; 9% to subsequent malignancies and 6% to cardiopulmonary disease. Estimated probability of relative survival was 62% at 5 years and 50% at 10 years from aHCT. On the other hand, the 5-year relative survival was 70, 75, 81 and 88% after having survived 1, 2, 5 and 10 years after aHCT, respectively. The cohort was at a 13.9-fold increased risk of death compared with the general population (95% confidence interval (CI)=13.1-14.8). The risk of death approached that of the general population for 10-year survivors (standardized mortality ratio (SMR)=1.4, 95% CI=0.9-1.9), with the exception of female Hodgkin's lymphoma patients transplanted before 1995 at age 40 years (SMR=6.0, 95% CI=1.9-14.0). Among those who had survived 10 years, nonrelapse-related mortality rates exceeded relapse-related mortality rates. This study provides clinically relevant survival estimates after aHCT, and helps inform interventional strategies.


Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adolescent , Adult , Aged , Child , Female , Hematologic Neoplasms/mortality , Humans , Male , Middle Aged , Transplantation, Autologous
3.
Biol Blood Marrow Transplant ; 18(8): 1273-80, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22306735

ABSTRACT

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , Inflammatory Breast Neoplasms/drug therapy , Inflammatory Breast Neoplasms/surgery , Peripheral Blood Stem Cell Transplantation/methods , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/pathology , Carboplatin/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Humans , Inflammatory Breast Neoplasms/pathology , Melphalan/administration & dosage , Middle Aged , Neoplasm Metastasis , Paclitaxel/administration & dosage , Survival Analysis , Thiotepa/administration & dosage , Treatment Outcome
4.
Ann Oncol ; 23(4): 1023-9, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21778300

ABSTRACT

BACKGROUND: Chemotherapy in combination with small-molecule epidermal growth factor receptor inhibitors has yielded inconsistent results. Based on preclinical models, we conducted a phase I trial of two schedules of lapatinib and vinorelbine. PATIENT AND METHODS: Patients had advanced solid tumors and up to two prior chemotherapeutic regimens. Patients were enrolled on two dose-escalating schedules of lapatinib, continuous (arm A) or intermittent (arm B), with vinorelbine on days 1, 8, and 15 of a 28-day cycle. Tumors from a subset of patients were evaluated for gene mutations and expression of targets of interest. RESULTS: Fifty-one patients were treated. The most common grade 3/4 toxic effects included leukopenia, neutropenia, and fatigue. Dose-limiting toxic effects were grade 3 infection, febrile neutropenia, and diarrhea (arm A) and bone pain and fatigue (arm B). The maximum tolerated dose was vinorelbine 20 mg/m(2) weekly and lapatinib 1500 mg daily (arm A) and vinorelbine 25 mg/m(2) weekly and lapatinib 1500 mg intermittently (arm B). One patient on each arm had a complete response; both had human epidermal growth factor receptor 2-positive breast cancer. In a subset of patients, lack of tumor PTEN expression correlated with a shorter time to progression. CONCLUSION: In an unselected population, two schedules of lapatinib and vinorelbine were feasible and well tolerated.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Prostatic Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Kaplan-Meier Estimate , Lapatinib , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Male , Middle Aged , PTEN Phosphohydrolase/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/mortality , Quinazolines/administration & dosage , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine
5.
Breast Cancer Res Treat ; 131(3): 899-906, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22042372

ABSTRACT

Inhibition of the HER-2 pathway via the monoclonal antibody trastuzumab has had a major impact in treatment of HER-2 positive breast cancer, but de novo or acquired resistance may reduce its effectiveness. The known interplay between the epidermal growth factor receptor (EGFR) and HER-2 receptors and pathways creates a rationale for combined anti-EGFR and anti-HER-2 therapy in HER-2 positive metastatic breast cancer (MBC), and toxicities associated with the use of multiple chemotherapeutic agents together with biological therapies may also be reduced. We conducted a prospective, single arm, phase I/II trial to determine the efficacy and toxicity of the combination of trastuzumab with the EGFR inhibitor gefitinib and docetaxel, in patients with HER-2 positive MBC. The maximum tolerated dose (MTD) was determined in the phase I portion. The primary end point of the phase II portion was progression-free survival (PFS). Immunohistochemical analysis of biomarker expression of the PKA-related proteins cAMP response element-binding protein (CREB), phospho-CREB and DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) plus t-DARPP (the truncated isoform of DARPP-32); PTEN; p-p70 S6K; and EGFR was conducted on tissue from metastatic sites. Nine patients were treated in the phase I portion of the study and 22 in the phase II portion. The MTD was gefitinib 250 mg on days 2-14, trastuzumab 6 mg/kg, and docetaxel 60 mg/m(2) every 21 days. For the 29 patients treated at the MTD, median PFS was 12.7 months, with complete and partial response rates of 18 and 46%, and a stable disease rate of 29%. No statistically significant correlation was found between response and expression of any biomarkers. We conclude that the combination of gefitinib, trastuzumab, and docetaxel is feasible and effective. Expression of the biomarkers examined did not predict outcome in this sample of HER-2 overexpressing metastatic breast cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Receptor, ErbB-2/antagonists & inhibitors , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/metabolism , Breast Neoplasms/mortality , Docetaxel , ErbB Receptors/antagonists & inhibitors , Female , Gefitinib , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Quinazolines/administration & dosage , Taxoids/administration & dosage , Trastuzumab , Treatment Outcome
6.
Breast Cancer Res Treat ; 132(3): 1063-72, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22200869

ABSTRACT

In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1-3, 8-10, and 15-17, plus paclitaxel (90 mg/m(2)) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and α-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Liver Neoplasms/secondary , Lung Neoplasms/secondary , Tubulin/metabolism , Acetylation , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bevacizumab , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Disease-Free Survival , Female , HSP90 Heat-Shock Proteins/metabolism , Humans , Hydroxamic Acids/administration & dosage , Kaplan-Meier Estimate , Middle Aged , Paclitaxel/administration & dosage , Protein Processing, Post-Translational/drug effects , Treatment Outcome , Vorinostat
7.
Oncogene ; 30(43): 4437-46, 2011 Oct 27.
Article in English | MEDLINE | ID: mdl-21532620

ABSTRACT

Breast cancer is genetically and clinically heterogeneous. Triple negative breast cancer (TNBC) is a subtype of breast cancer that is usually associated with poor outcome and lack of benefit from targeted therapy. We used microarray analysis to perform a pathway analysis of TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), low density lipoprotein receptor-related protein 6 and transcription factor 7 (TCF7) was observed in TNBC, and we directed our focus to the Wnt pathway receptor, FZD7. To validate the function of FZD7, FZD7shRNA was used to knock down FZD7 expression. Notably, reduced cell proliferation and suppressed invasiveness and colony formation were observed in TNBC MDA-MB-231 and BT-20 cells. Study of the possible mechanism indicated that these effects occurred through silencing of the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of ß-catenin and decreased transcriptional activity of TCF7. In vivo studies revealed that FZD7shRNA significantly suppressed tumor formation, through reduced cell proliferation, in mice bearing xenografts without FZD7 expression. Our findings suggest that FZD7-involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC, and thus, FZD7 shows promise as a biomarker and a potential therapeutic target for TNBC.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Frizzled Receptors/physiology , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , Female , Humans , Neoplasms, Hormone-Dependent , Protein Array Analysis , Signal Transduction , Up-Regulation , Wnt Signaling Pathway/physiology
8.
Ann Oncol ; 20(12): 2000-6, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19564171

ABSTRACT

BACKGROUND: Although secondary acute leukemias and myelodysplasia are the known complications of adjuvant chemotherapy for breast cancer, the treatment outcome of these secondary malignancies is presently unclear. We examined the clinical and pathological features as well as the treatment results of a series of patients with acute leukemia/myelodysplasia arising after adjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: Patients referred to our institution during a 5-year period for treatment of acute leukemia/myelodysplasia and who had received adjuvant chemotherapy for breast cancer are included. Leukemia-free survival for the whole group and for patients who underwent hematopoietic stem cell transplantation (HSCT) was estimated. RESULTS: Fifteen women (14 with acute leukemia and one with myelodysplasia) were identified. Seven of 15 patients had received an anthracycline, cyclophosphamide and a taxane. Ten patients developed acute leukemia/myelodysplasia with a latency period of 2 years or less from initiation of chemotherapy. Although mixed-lineage leukemia (MLL) rearrangement was the commonest chromosomal abnormality (8 of 15 patients), various other chromosomal abnormalities were also detected. Twelve of 15 patients underwent HSCT (11 allogeneic and one autologous). Eleven of these 12 patients who underwent HSCT were in remission at a median follow-up of 20.4 months (range 4.4-53.3 months). CONCLUSION: Durable remissions can be achieved in patients who develop acute leukemia/myelodysplasia secondary to adjuvant chemotherapy for breast cancer and are able to undergo allogeneic HSCT. Our results indicate that HSCT should be an early consideration in the management of such patients who are suitable candidates for the procedure.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Hematopoietic Stem Cell Transplantation , Leukemia/surgery , Myelodysplastic Syndromes/surgery , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Child , Female , Humans , Leukemia/chemically induced , Middle Aged , Myelodysplastic Syndromes/chemically induced , Remission Induction
10.
Ann Oncol ; 19(11): 1853-9, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18641005

ABSTRACT

BACKGROUND: Patients with high-risk primary breast cancer remain at high risk for relapse. More precise prognostic and predictive tools are needed to improve treatment of such patients. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded tumors from 239 high-risk breast cancer patients were examined for expression of human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), estrogen receptor, progesterone receptor, Ki-67, p16, p21, p27, and p53 by immunohistochemistry. Gene expression of EGFR, HER2, glutathione S-transferase-Pi (GSTP1), excision repair cross complementation1 (ERCC1), p21, beta-tubulin-3, multidurg resistance (MDR1), cyclooxygenase2 (COX2), and cyclin-E was measured by RT-PCR. RESULTS: Eighty percent of patients presented with locally advanced, or > or =10 axillary nodal metastasis, and 20% with inflammatory breast cancer. The median age was 46 years (26-62 years) and the median number of involved axillary lymph nodes was 12 (0-42). At a median follow-up of 86 months, relapse-free survival (RFS) and overall survival for the entire group were 50% (95% CI 43% to 57%) and 62% (95% CI 56% to 69%). Multivariate Cox stepwise analysis resulted in a simple model for RFS consisting only of p21 expression, EGFR expression assessed by RT-PCR, and number of axillary nodal metastases. CONCLUSION: A prognostic model on the basis of the expression of a limited number of proteins and genes may help to guide target-specific therapies in patients with high-risk breast cancer.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , ErbB Receptors/biosynthesis , Adult , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Growth Processes/physiology , Cohort Studies , Cyclin-Dependent Kinase Inhibitor p21/genetics , Disease-Free Survival , ErbB Receptors/genetics , Female , Gene Expression , Gene Expression Profiling , Humans , Immunohistochemistry , Middle Aged , Neoplasm Staging , Receptor, ErbB-2/biosynthesis , Receptor, ErbB-2/genetics , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors
11.
Int J Gynecol Cancer ; 17(2): 373-8, 2007.
Article in English | MEDLINE | ID: mdl-17362315

ABSTRACT

The purpose of this study was to estimate the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN), in recurrent ovarian cancer (OC), and to measure their effects on CBDCA pharmacokinetics. OC patients relapsing following platinum-based chemotherapy received CBDCA area under the curve (AUC 3) with CSA and IFN, every 3 weeks. The pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Thirty patients received 84 courses of therapy. Three partial responses were observed. Nine patients were stable for >4 months. Toxicity was similar to that observed in our previously reported phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean end of infusion CSA level (high-performance liquid chromatographic assay [HPLC]) was 1109 +/- 291 microg/mL (mean +/- SD). CBDCA pharmacokinetics revealed a measured AUC of 3.61 versus a targeted AUC of 3, suggesting a possible effect of IFN on CBDCA levels versus errors in the estimation of CBDCA clearance using measured creatinine clearance. Steady-state levels of >1 microg/mL CSA (HPLC assay) are achievable in vivo. Insufficient clinical resistance reversal was observed in this study to warrant further investigation of this combination.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , California , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carboplatin/pharmacokinetics , Cyclosporine/administration & dosage , Cyclosporine/adverse effects , Cyclosporine/pharmacokinetics , Drug Resistance, Neoplasm/drug effects , Female , Humans , Infusions, Intravenous , Injections, Subcutaneous , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Interferon-alpha/pharmacokinetics , Middle Aged , Treatment Outcome
12.
Pharmacogenomics J ; 7(5): 362-5, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17224914

ABSTRACT

Paclitaxel is commonly used in the treatment of breast cancer. Variability in paclitaxel clearance may contribute to the unpredictability of clinical outcomes. We assessed genomic DNA from the plasma of 93 patients with high-risk primary or stage IV breast cancer, who received dose-intense paclitaxel, doxorubicin and cyclophosphamide. Eight polymorphisms in six genes associated with metabolism and transport of paclitaxel were analyzed using Pyrosequencing. We found no association between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance. However, patients homozygous for the CYP1B1*3 allele had a significantly longer progression-free survival than patients with at least one Valine allele (P=0.037). This finding could reflect altered paclitaxel metabolism, however, the finding was independent of paclitaxel clearance. Alternatively, the role of CYP1B1 in estrogen metabolism may influence the risk of invasive or paclitaxel resistant breast cancer in patients carrying the CYP1B1*3 allele.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Cytochrome P-450 Enzyme System/genetics , Gene Expression Regulation, Neoplastic , Polymorphism, Genetic , Adult , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Aryl Hydrocarbon Hydroxylases , Biological Transport/genetics , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cyclophosphamide/administration & dosage , Cytochrome P-450 CYP1B1 , Cytochrome P-450 Enzyme System/metabolism , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Gene Frequency , Homozygote , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Treatment Outcome
13.
Bone Marrow Transplant ; 37(9): 825-9, 2006 May.
Article in English | MEDLINE | ID: mdl-16565743

ABSTRACT

Although autologous stem cell transplant is an effective therapy for patients with multiple myeloma and extends progression-free survival (PFS) and overall survival (OS), patients show a continued pattern of recurrent disease. Twenty-nine patients were enrolled in a phase II study investigating the tolerability and efficacy of maintenance thalidomide following single autologous peripheral blood stem cell transplant. Six to eight weeks after transplant, patients were started on maintenance thalidomide at 50 mg a day. The dose was gradually escalated to a target dose of 400 mg a day and continued until disease progression or 6 months after achieving complete remission (CR) for a maximum total duration of 18 months. At 6 months, 13 patients (45%) achieved CR or near complete remission (positive immunofixation without any evidence of disease). The estimated 2-year OS was 83% and PFS was 49%. Median tolerated dose of thalidomide was 200 mg a day. In conclusion, thalidomide as maintenance therapy is feasible and may improve outcome after single autologous stem cell transplant.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Multiple Myeloma/therapy , Stem Cell Transplantation , Thalidomide/therapeutic use , Aged , Combined Modality Therapy , Disease Progression , Female , Humans , Male , Middle Aged , Multiple Myeloma/blood supply , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Neoplasm Staging , Stem Cell Transplantation/adverse effects , Survival Analysis , Survivors , Thalidomide/toxicity , Time Factors , Transplantation, Autologous , Treatment Outcome
14.
Eur J Surg Oncol ; 30(6): 650-7, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15256240

ABSTRACT

AIM: We describe the feasibility of combining infusional 5-fluorouracil (5-FU) with intraoperative radiation therapy (IORT). METHODS: Patients with surgically resectable locally advanced gastrointestinal cancers were treated concurrently during surgery with IORT and a 72 h infusion of 5-FU. Patients without previous external beam radiation therapy (EBRT) were subsequently treated with EBRT (40-50Gy) concurrent with a 21-day continuous infusion of 5-FU. Pancreatic, gastric, duodenal, ampullary, recurrent colorectal, and recurrent anal cancer were included. RESULTS: During IORT/5-FU, no chemotherapy-related grade III or IV hematologic or gastrointestinal toxicity was noted. Post-surgical recovery or wound healing was not affected. One of nine patients who received post-operative radiation required a treatment break. During follow-up, there were more complications in patients with pelvic tumours, especially those with previous radiation. Nine patients have had local and/or local regional recurrences, two of these in the IORT field. CONCLUSIONS: Treatment with a combination of IORT and 5-FU followed by EBRT and 5-FU is feasible. However, long-term complications may be increased in previously irradiated recurrent pelvic tumours.


Subject(s)
Adenocarcinoma/therapy , Antineoplastic Agents/administration & dosage , Digestive System Surgical Procedures/methods , Fluorouracil/administration & dosage , Gastrointestinal Neoplasms/therapy , Radiotherapy/methods , Adult , Aged , Combined Modality Therapy , Feasibility Studies , Female , Humans , Infusions, Intravenous , Intraoperative Period , Male , Middle Aged , Pilot Projects , Radiotherapy, High-Energy , Treatment Outcome
15.
Bone Marrow Transplant ; 33(11): 1123-9, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15064696

ABSTRACT

In an attempt to decrease toxicity in high-risk patients undergoing unrelated donor hematopoietic stem cell transplantation (URD HSCT), we tested a combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis with the reduced-intensity conditioning regimen fludarabine/melphalan (Flu/Mel). A total of 22 adult patients with advanced myeloid (n=15) and lymphoid (n=7) malignancies were treated. All patients received Flu 25 mg/m2 for 5 days and Mel 140 mg/m2, with CSP 3 mg/kg daily and MMF 15 mg/kg three times a day. The median age was 49 years (range 18-66). Durable engraftment was seen in all but one patient with myelofibrosis. The 1-year nonrelapse mortality was 32%, 27% from GVHD. The cumulative incidence of acute GVHD grade 2-4 and 3-4 was 63 and 41%, respectively. With a median follow-up of 18 months, the disease-free survival (DFS) and overall survival (OS) are 55 and 59%, respectively. For patients with AML and MDS (n=14), the DFS and OS is 71%. For patients undergoing a second transplant (n=14), the DFS and OS is 57%. In conclusion, this regimen is associated with acceptable toxicity but high rates of GVHD in high-risk patients undergoing URD HSCT. Encouraging disease control for patients with advanced myeloid malignancies was observed.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/toxicity , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Mycophenolic Acid/analogs & derivatives , Premedication/methods , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclosporine/administration & dosage , Female , Graft Survival , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/complications , Hematologic Neoplasms/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Male , Melphalan/administration & dosage , Middle Aged , Mycophenolic Acid/administration & dosage , Opportunistic Infections , Prospective Studies , Survival Analysis , Tissue Donors , Treatment Outcome , Vidarabine/administration & dosage
16.
Biol Blood Marrow Transplant ; 9(12): 766-71, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14677116

ABSTRACT

The prognosis of patients with primary refractory acute myelogenous leukemia (AML) is poor. Our initial report suggested that some patients could achieve durable remission after allogeneic stem cell transplantation (SCT). Herein, we update our initial experience and report further analysis of this group of patients to determine whether there are pre-SCT prognostic factors predictive of posttransplantation relapse and survival. We reviewed the records of 68 patients who consecutively underwent transplantation at the City of Hope Cancer Center with allogeneic SCT for primary refractory AML between July 1978 and August 2000. Potential factors associated with overall survival and disease-free survival were examined. With a median follow-up of 3 years, the 3-year cumulative probabilities of disease-free survival (DFS), overall survival (OS), and relapse rate for all 68 patients were 31% (95% confidence interval [CI], 20%-42%), 30% (95% CI, 18%-41%), and 51% (95% CI, 38%-65%), respectively. In multivariate analysis, the only variables associated with shortened OS and DFS included the use of an unrelated donor as the stem cell source (relative risk, 2.23 [OS] and 2.05 [DFS]; P =.0005 and.0014, respectively) and unfavorable cytogenetics before SCT (relative risk: 1.68 [OS] and 1.58 [DFS]; P =.0107 and.0038, respectively). Allogeneic SCT can cure approximately one third of patients with primary refractory AML. Cytogenetic characteristics before SCT correlate with transplantation outcome and posttransplantation relapse.


Subject(s)
Cytogenetic Analysis , Hematopoietic Stem Cell Transplantation/mortality , Leukemia, Myeloid, Acute/therapy , Adolescent , Adult , Bone Marrow Transplantation/mortality , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Salvage Therapy , Survival Analysis , Transplantation, Homologous , Treatment Outcome
17.
Biol Blood Marrow Transplant ; 9(10): 649-56, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14569561

ABSTRACT

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m(2)) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.


Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Transplantation Immunology , Adult , Combined Modality Therapy , Female , Graft Survival , Hematologic Neoplasms/complications , Hematologic Neoplasms/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Male , Middle Aged , Recurrence , Survival Analysis , Transplantation, Autologous , Transplantation, Homologous , Treatment Failure , Treatment Outcome
18.
Br J Cancer ; 87(3): 281-8, 2002 Jul 29.
Article in English | MEDLINE | ID: mdl-12177795

ABSTRACT

We report on a predictive model of long-term outcome in 114 high-risk breast cancer patients treated with high-dose chemotherapy between 1989 and 1994. Paraffin-blocks from 90 of the 114 primaries were assessed for the presence of five risk factors: grade, mitotic index, protein expression of p53, HER2/neu, and oestrogen/progesterone receptor status; we could analyse the effect of risk factors in 84 of these 90 tumours. Seven-year relapse-free and overall survival was 58% (95% confidence interval 44-74%) and 82% (95% confidence interval 71-94%) vs 33% (95% confidence interval 21-52%) and 41% (95% confidence interval 28-60%) for patients whose primary tumours displayed > or =3 risk factors vs patients with < or =2 risk factors. For the entire group of 168 high-risk breast cancer patients, inflammatory stage IIIB disease and involved post-mastectomy margins were associated with decreased relapse-free survival and overall survival; patients treated with non-doxorubicin containing standard adjuvant therapy experienced worse overall survival (RR, 2.08; 95% confidence interval 1.04 to 4.16; P=0.04), while adjuvant tamoxifen improved overall survival (RR, 0.65; 95% confidence interval 0.41-1.01; P=0.054). Future trial designs and patient selection for studies specific for high-risk breast cancer patients should include appropriate prognostic models. Validation of such models could come from recently completed randomised, prospective trials.


Subject(s)
Breast Neoplasms/drug therapy , Adult , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Staging , Prognosis , Survival Rate , Treatment Outcome
19.
Biol Blood Marrow Transplant ; 7(5): 284-93, 2001.
Article in English | MEDLINE | ID: mdl-11400951

ABSTRACT

We evaluated the feasibility of tandem-cycle high-dose chemotherapy (HDCT) with cisplatin, melphalan, and peripheral blood progenitor cells (PBPCs). Fifty patients with high-risk primary (n = 17) or stage IV breast cancer (n = 29) or other malignancies (n = 4) received 2 cycles of intravenous melphalan, 20 to 151.8 mg/m2, and cisplatin, 200 mg/m2, followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF. Starting at 40 mg/m2 of melphalan, patients also received PBPCs. Delayed platelet recovery defined the maximum tolerated dose (MTD) for melphalan at 101.2 mg/m2 per cycle. There were no treatment-related deaths. Cycle 2 was delivered at a median of 1.7 months after cycle 1; 72% of patients treated at the MTD received both cycles. Cycle 2 was omitted when patients refused it or had disease progression or toxicities, primarily prolonged thrombocytopenia. Complete response rates in stage IV breast cancer patients increased from 28% pre-HDCT to 55% after cycle 2. At a median follow-up of 4.6 years (range, 1.5-8.1 years), 11 of 29 patients with stage IV breast carcinoma were alive with 5-year projected progression-free and overall survival rates of 19% (95% confidence interval [CI], 7%-41%) and 39% (95% CI, 20%-62%), respectively. Five-year projected progression-free and overall survival rates for patients with stage IV breast cancer in complete response following HDCT versus all others were 35% (95% CI, 15%-70%) versus 0% (P = .01) and 61% (95% CI, 35%-91%) versus 10% (95% CI, 2%-60%) (P = .003; log-rank test), respectively. Estrogen-receptor positivity was predictive of reduced risk of progression (relative risk [RR], 0.25; 95% CI, 0.10-0.65; P = .003) and death (RR, 0.27; 95% CI, 0.10-0.72; P = .009) after adjusting for response status. Five-year projected relapse-free and overall survival rates were 71% (95% CI, 43%-96%) and 82% (95% CI, 56%-100%), respectively, for the 17 patients with high-risk primary breast cancer. Tandem-cycle high-dose melphalan and cisplatin with PBPCs is feasible. Preliminary data suggest significant activity in selected patients with stage IV responding breast carcinoma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adult , Antineoplastic Combined Chemotherapy Protocols/toxicity , Breast Neoplasms/complications , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Cisplatin/administration & dosage , Cisplatin/toxicity , Disease-Free Survival , Feasibility Studies , Female , Follow-Up Studies , Graft Survival , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Maximum Tolerated Dose , Melphalan/administration & dosage , Melphalan/toxicity , Middle Aged , Neoplasm Staging , Survival Analysis , Treatment Outcome
20.
Br J Cancer ; 84(12): 1591-8, 2001 Jun 15.
Article in English | MEDLINE | ID: mdl-11401310

ABSTRACT

We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with >or= 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150-775 mg/m(2)infused over 24 hours, doxorubicin 165 mg/m(2)as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg(-1). There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m(2) dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan-Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51-83%) and 77% (95% CI; 64-93%). Paclitaxel up to 725 mg/m(2) infused over 24 hours in combination with with doxorubicin 165 mg/m(2) and cyclophosphamide 100 mg kg(-1) is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma, Ductal, Breast/drug therapy , Hematopoietic Stem Cell Transplantation , Paclitaxel/adverse effects , Adult , Area Under Curve , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Cyclophosphamide/administration & dosage , Disease-Free Survival , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Female , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Staging , Paclitaxel/pharmacokinetics , Peripheral Nervous System Diseases/chemically induced , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL
...