Phase I study investigating the safety and feasibility of combining imatinib mesylate (Gleevec) with sorafenib in patients with refractory castration-resistant prostate cancer.

BACKGROUND: Determining the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of sorafenib (S) plus imatinib (IM) in castration-resistant prostate cancer (CRPC) patients. METHODS: Refractory CRPC patients were enrolled onto this 3+3 dose escalation designed study. Imatinib pharmacokinetics (PK) were determined on day 15, 4 h post dose with a validated LC-MS assay. RESULTS: Seventeen patients were enrolled; 10 evaluable (6 at 400 mg S qd with 300 mg IM qd (DL0) and 4 at 400 mg S bid with 300 mg IM qd (DL1)); inevaluable patients received <1 cycle. The median age was 73 (57-89); median prostatic serum antigen was 284 ng ml(-1) (11.7-9027). Median number of prior non-hormonal therapies was 3 (1-12). Dose-limiting toxicities were diarrhoea and hand-foot syndrome. Maximum tolerated dose was 400 mg S and 300 mg IM both daily. No biochemical responses were observed. Two patients had stable disease by RECIST. Median time to progression was 2 months (1-5). Median OS was 6 months (1-30+) with 3/17 patients (17%) alive at 21 months median follow-up. Ten patients had PK data suggesting that S reduced IM clearance by 55%, resulting in 77% increased exposure (P=0.005; compared with historical data). CONCLUSION: This is the first report showing that S+IM can be administered in CRPC at a dose of 400 mg S and 300 mg IM, daily.

Hematopoietic SCT for mantle cell lymphoma: is it the standard of care?

The role of hematopoietic SCT (HSCT) in mantle cell lymphoma (MCL) remains controversial. Most studies that support the utility of this approach were small phase II single-institution studies with highly selected patient populations. Furthermore, recent evidence suggesting initial observation as opposed to immediate therapy in MCL, coupled with the availability of newer therapeutic agents, complicates the role of HSCT and argues for conducting large phase III studies. In this review, we discuss the limitation of current evidence and the lack of large definitive studies. We then analyze the data on HSCT in relapsed MCL and as a frontline approach propose applying the new prognostic index, MIPI (MCL International Prognostic Index), in the decision making.

Docetaxel and oxaliplatin as first-line therapy for advanced non-small cell lung cancer: a phase II trial.

We sought to evaluate the safety and efficacy of docetaxel and oxaliplatin combination as first-line therapy for patients with stage IV or wet III(B )non small cell lung cancer. Patients received oxaliplatin at 85 mg/m(2) intravenously over 2 hours on days 1 and 15 along with docetaxel at 30 mg/m(2) intravenously on days 1 and 8; both given every 28 days. Cycles were repeated every 4 weeks for a maximum of 6. Fifteen patients were enrolled for an overall response rate of 50% (95% CI 21-74%). Median progression-free survival was 2.4 months with a 1-year progression free survival of 10%. Median overall survival was 7.9 months with 49% of patients alive at 1 year. Most common toxicities were nausea, vomiting, and dehydration. This combination has notable activity in advanced non-small cell lung cancer with a favorable toxicity profile.

Allogeneic hematopoietic cell transplantation for metastatic breast cancer.

We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.

Transplantation of CD34+ peripheral blood cells selected using a fully automated immunomagnetic system in patients with high-risk breast cancer: results of a prospective randomized multicenter clinical trial.

Tumor contamination of autologous peripheral blood stem/progenitor cell grafts occurs in a substantial proportion of high-risk breast cancer patients, and the possibility that such contamination may contribute to relapse has focused attention on methods for removal of the contaminating cells prior to transplantation. One such approach is positive selection of CD34+ cells. A fully automated immunomagnetic cell selection system has recently been introduced to facilitate the positive selection process. A multicenter randomized clinical trial was designed to evaluate the capacity of CD34+ cells isolated using the fully automated system to support prompt hematopoietic reconstitution following high-dose chemotherapy in high-risk breast cancer patients, as well as to assess the safety and tolerability of the CD34+ cell transplants. In recipients of isolated CD34+ cells, the median time to an absolute neutrophil count > or =500/microl was 10 days, a value identical to that observed in patients receiving unfractionated apheresis collections. In the isolated CD34+ cell recipients median time to a platelet count > or =20 000/microl was 12 days, compared with 10 days in the unfractionated cell group. There were no statistically significant differences between the groups in median time to neutrophil or platelet engraftment. Infusion of autologous cells was well tolerated by the study groups. There were no inter-group differences in the incidence of infections, need for platelet transfusions, or duration of hospitalization. Isolated CD34+ cells were high in purity and sufficient in number for use in autologous transplantation. The fully automated immunomagnetic cell selection system affords an efficient and time-saving option for isolation of CD34+cells to be used as autologous grafts in high-risk breast cancer patients, and the isolated CD34+ cells support undelayed hematopoietic reconstitution.

Delphi-panel analysis of appropriateness of high-dose chemotherapy and blood cell or bone marrow autotransplants in women with breast cancer.

BACKGROUND: There is controversy whether high-dose chemotherapy and a blood cell or bone marrow autotransplant is a better treatment than conventional-dose chemotherapy for women with local/regional or metastatic breast cancer. Subject selection and time-to-treatment biases make definitive comparison impossible. Recent results of randomized trials are contradictory. OBJECTIVE: Determine appropriateness of high-dose chemotherapy and a blood cell or bone marrow autotransplant in women with breast cancer. PANELISTS: Nine breast cancer experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of 'breast cancer' and 'chemotherapy' and/or 'blood cell' or 'bone marrow transplants'. PROCESS: We used a modified Delphi-panel group judgement process. Clinical variables were permuted to define 2058 clinical settings. Each panelist rated appropriateness of high-dose therapy and an autotransplant versus conventional therapy on a 9-point ordinal scale (1: most inappropriate, 9: most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. CONCLUSIONS: In women with local/regional breast cancer autotransplants were rated: 1) appropriate in those with > or = 10 cancer-involved lymph nodes; 2) uncertain in those with 4-9 cancer-involved nodes; and 3) inappropriate in women with < or = 3 cancer-involved lymph nodes. In women with metastatic breast cancer autotransplants were rated: 1) appropriate in those with metastases to 'favorable' sites (skin, lymph node, pleura) and a complete or partial response to chemotherapy; 2) uncertain in women with metastases to 'unfavorable' sites (lung, liver, or central nervous system) and a complete response to chemotherapy or those with bone metastases and a complete or partial response or stable disease after chemotherapy; and 3) inappropriate in other settings.

Factors correlated with progression-free survival after high-dose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer.

CONTEXT: Women with breast cancer are the most frequent recipients of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (autotransplants) in North America. Despite widespread use, controversy exists about the benefits of and appropriate patients for this therapy. OBJECTIVE: To determine factors associated with disease progression or death after autotransplantation in women with metastatic breast cancer. DESIGN: Analysis of data collected retrospectively (January 1989 to 1992) and prospectively (1992 through January 1995) for the Autologous Blood and Marrow Transplant Registry. SETTING: Sixty-three hospitals in North America, Brazil, and Russia. PARTICIPANTS: A total of 1188 consecutive women aged 18 to 70 years receiving autotransplants for metastatic or locally recurrent breast cancer, with a median follow-up of 291/2 months. MAIN OUTCOME MEASURE: Time to treatment failure (disease progression, disease recurrence, or death) after autotransplantation. RESULTS: Factors associated with significantly (P<.05) increased risk of treatment failure in a Cox multivariate analysis included age older than 45 years (relative hazard, 1.17; 95% confidence interval [CI], 1.02-1.33), Karnofsky performance score less than 90% (1.27; 95% CI, 1.07-1.51), absence of hormone receptors (1.31; 95% CI, 1.15-1.51), prior use of adjuvant chemotherapy (1.31; 95% CI, 1.10-1.56), initial disease-free survival interval after adjuvant treatment of no more than 18 months (1.99; 95% CI, 1.62-2.43), metastases in the liver (1.47; 95% CI, 1.20-1.80) or central nervous system (1.56; 95% CI, 0.99-2.46 [approaches significance]) vs soft tissue, bone, or lung, 3 or more sites of metastatic disease (1.32; 95% CI, 1.13-1.54), and incomplete response vs complete response to standard-dose chemotherapy (1.65; 95% CI, 1.36-1.99). Receiving tamoxifen posttransplantation was associated with a reduced risk of treatment failure in women with hormone receptor-positive tumors (relative hazard, 0.60; 95% CI, 0.47-0.87). Women with no risk factors (n = 38) had a 3-year probability of progression-free survival of 43% (95% CI, 27%-61 %) vs 4% (95% CI, 2%-8%) for women with more than 3 risk factors (n = 343). CONCLUSION: These data indicate that some women are unlikely to benefit from autotransplantation and should receive this treatment only after being provided with prognostic information and in the context of clinical trials attempting to improve outcome.

Phase II trial of paclitaxel and topotecan with granulocyte colony-stimulating factor support in stage IV breast cancer.

PURPOSE: This multicenter phase II trial investigated the efficacy and safety of a combination of paclitaxel and topotecan in patients with pretreated metastatic breast cancer. Plasma levels of paclitaxel and topotecan were obtained during cycle 1 to correlate pharmacokinetic parameters with toxicity. PATIENTS AND METHODS: Paclitaxel was administered intravenously (i.v.) at 230 mg/m2 over 3 hours on day 1 followed by topotecan 1.0 mg/m2 i.v. over 30 minutes on days 1 to 5. Patients received an abbreviated premedication regimen that consisted of ranitidine 50 mg, diphenhydramine 50 mg, and a single 20-mg dose of dexamethasone, all administered i.v. 30 minutes before paclitaxel. Granulocyte colony-stimulating factor (GCSF) was administered at 5 micrograms/kg/d subcutaneously starting on day 6 and continuing until the absolute granulocyte count (AGC) was greater than 10,000/microL. Plasma paclitaxel and topotecan concentrations were assessed during the first cycle using limited-sampling strategies. RESULTS: Seventeen patients were treated. The majority had visceral metastases. Four patients experienced neutropenic fever and one had mild bronchospasm. Only one partial response (PR) was observed. Nadir AGC correlated strongly with both duration of paclitaxel levels greater than 0.05 mumol/L and maximum concentration (Cmax) of paclitaxel. CONCLUSION: This regimen does not produce a response rate superior to that expected with single-agent paclitaxel at doses that do not require growth factor support.

High-dose chemotherapy consolidation with autologous stem cell rescue in metastatic breast cancer: a 10-year experience.

One hundred women with metastatic breast cancer (MBC) underwent high-dose chemotherapy with autologous stem cell rescue at our institution beginning in 1986. The patients underwent induction chemotherapy from June 1986 to December 1993. Patients who showed stable or responsive disease underwent HDC with cyclophosphamide (CY) at 7.5 g/m2 and thiotepa (TPA) at 675 mg/m2 or the same doses of CY and TPA with carmustine at 450 mg/m2. The source of stem cell rescue was either BM alone, BM and G-CSF-mobilized peripheral blood progenitor cells (PBPC) or PBPC alone if patients had BM involvement with MBC. With a median follow-up of 62 months (range 1-109 months), median survival from reinfusion was 16 months with a 5-year survival of 19+/-4%. The median event-free survival (EFS) was 8 months with a 5-year EFS of 11+/-3%. Patients achieving a complete response to induction therapy showed a higher 5-year EFS from reinfusion of 31+/-8% in contrast to 3+/-3% (P = 0.006) for patients who achieved a partial response to induction therapy prior to HDC. Marrow involvement or source of stem cell rescue did not affect outcome. Our mature results confirm that high-dose chemotherapy with autologous stem cell rescue can confer a prolonged DFS in a subset of women with MBC. However, the high rate of relapse remains a universally disturbing problem in this patient population.

[Malignant neuroleptic syndrome, medical-psychiatric approach]. / Sindrome neuroléptico maligno, aproximación médico-psiquiátrica.

We report the case of a 42 years old male, with a bipolar disorder and receiving lithium therapy, valproic acid and clonazepam. Due to an exacerbation of his underlying disease, he was admitted to a psychiatric clinic and received 50 mg of intramuscular chlorpromazine in two occasions. Afterwards, the patient had an alteration of consciousness, fever reaching 39 degrees C and generalized muscular rigidity. Laboratory work-up showed a normal brain CT scan, a diffuse slowness in the EEG and a creatinphosphokinase that reached values of 3.040 U/l. He was transferred to an intensive care unit and treated with sodium dantrolene and bromocriptine, obtaining a good clinical response.

[Relevance of the thyroid function assessment in psychiatric patients]. / Relevancia del estudio tiroideo en pacientes con trastornos psiquiátricos.

BACKGROUND: Thyroid dysfunction is frequent in psychiatric outpatients and the correction of their endocrine abnormalities seems to improve the response to psychopharmacologic treatment. AIM: To retrospectively explore the frequency of thyroid abnormalities in psychiatric outpatients. MATERIAL AND METHODS: Clinical charts and thyroid assessment of 102 psychiatric patients aged 40.8 +/- 15 years old (28 male) seen between April 1995 and September 1996 were reviewed. Endocrine diagnosis was made according to international criteria and psychiatric diagnosis was made by a single psychiatrist following DSM IV criteria. RESULTS: Forty patients (39.2%) had thyroid abnormalities. Thirteen (12.7%) had a diagnosis of thyroid problems and were in treatment before they came to the psychiatric clinic. Sixteen patients had hypothyroidism (40%), seven had subclinical hypothyroidism (17.5%), 12 were euthyroid but had goiter or positive thyroid antibodies (30%) and 5 individuals had hyperthyroidism (12.5%). The most frequent thyroid abnormality was the presence of positive thyroid antibodies in 16 cases (15.7%). No specific association was found between psychiatric and endocrine diagnoses. CONCLUSIONS: The design of this study prevents to draw conclusions about prevalence of thyroid alterations in psychiatric patients. Nevertheless results support the need for routine thyroid assessment in this specific population.

Her2/neu overexpression is associated with treatment failure in women with high-risk stage II and stage IIIA breast cancer (>10 involved lymph nodes) treated with high-dose chemotherapy and autologous hematopoietic progenitor cell support following standard-dose adjuvant chemotherapy.

Twenty-five patients with high-risk stage II and IIIA breast cancer (>10 or more involved lymph nodes) were treated with six cycles of standard-dose chemotherapy (5-fluorouracil, doxorubicin, and cyclophosphamide) followed by high-dose chemotherapy (2.5 g/m2 cyclophosphamide for 3 days and 225 mg/m2 thiotepa for 3 days) with autologous hematopoietic progenitor cell support. The actuarial relapse free survival at 3 years is 80%; the actuarial survival at 3 years is 96%. Four patients relapsed systemically between 6 and 18 months; all four patients who relapsed had breast cancers that overexpressed Her2/neu. In contrast, none of the 21 patients who had no or borderline overexpression of Her2/neu relapsed (P = 0.00004, Fisher's exact test). Patients with high-risk stage II and IIIA breast cancer who have overexpression of Her2/neu appear to be at a high risk for relapse, even when treated with high-dose chemotherapy and autologous hematopoietic progenitor cell support.

A phase II study of cyclophosphamide followed by PIXY321 as a means of mobilizing peripheral blood hematopoietic progenitor cells.

Fourteen patients with stage II-IV breast cancer were enrolled in a phase II study of cyclophosphamide followed by PIXY321 as a means of mobilizing peripheral blood progenitor cells (PBPC). All 14 women tolerated PIXY321 well, with the predominant toxicities being erythema at the injection site, fever, and arthralgias. A median of two aphereses yielded a mean of 1.3 x 10(8) mononuclear cells/kg, 8.9 x 10(4) colony-forming units-granulocyte/macrophage (CFU-GM)/kg, and 4.5 x 10(6) CD34+ cells/kg. All 14 patients underwent high-dose chemotherapy with PBPC support, the median day to ANC >500 cells/microliter was 10.6, and the median day to platelets >20,000 cells/microliter was 13. The day of 90th percentile platelet recovery was 15. When compared to PBPCs mobilized by cyclophosphamide followed by GM-CSF, the use of PIXY321 may confer an advantage of enhanced platelet recovery.

Tandem high-dose chemotherapy supported by hematopoietic progenitor cells yields prolonged survival in stage IV breast cancer.

The aim of this phase II study was to determine the feasibility of using two (tandem) courses of high-dose alkylating agents with bone marrow or peripheral blood progenitor cell support in women with stage IV breast cancer. Women with stage IV breast cancer who had achieved a CR or PR during conventional chemotherapy were enrolled in a phase II trial of high-dose cyclophosphamide 7500 mg/m2 and thiotepa 675 mg/m2 (C+T) followed within 180 days by high-dose melphalan (M) 140 mg/m2. Bone marrow and/or GM-CSF mobilized peripheral blood hematopoietic progenitor cells were used to support high-dose C+T and high-dose M. Twenty-seven women were enrolled in this trial. The median age was 45 years (range 32-56). The median PS was 0 and all patients had achieved either a CR (4/27, 15%) or PR (23/27, 85%) to conventional chemotherapy. All 27 women underwent high dose C+T. The predominant toxicities were mucositis (81%), and diarrhea (81%); two patients (7%) died from infectious complications. Following C+T, the median time to hematologic recovery for neutrophils (ANC > 500 cells/mu 1) was 12 days and for platelets (>20 000 cell/mu 1), 23 days. Following C+T, 18 of 22 patients received high dose M; the predominant toxicities were nausea, vomiting (70%), and mucositis (91%). The median time to hematologic recovery for the ANC was 13 days and for platelets, 18 days. The overall response after high dose C+T and high dose M was 67% (CR, 15/27 patients (56%) and PR* (complete resolution of all measurable disease but persistent lytic disease or positive bone scan) 3/27 patients (11%). With median follow-up of 24 months, the actuarial freedom from relapse or treatment failure is 56% at 24 months. At 30 months 56% of patients are alive. For patients who achieve a CR or PR* the actuarial freedom from relapse or treatment failure at 24 months is 88%. In women with stage IV breast cancer who attain a CR or PR to conventional chemotherapy, tandem high-dose chemotherapy with ABMT can lead to prolonged relapse-free survival.

A phase I-phase II study of vinorelbine with cisplatin, 5-fluorouracil, and leucovorin for advanced non-small cell lung cancer.

PURPOSE: The combination of cisplatin, 5-fluorouracil, and leucovorin (PFL) has been reported to have a 29% response rate in advanced non-small cell lung cancer. Vinorelbine, a semi-synthetic vinca alkaloid, has also been reported to have single-agent activity in this disease. We designed a phase I-II study in which escalating doses of vinorelbine were added to PFL to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine, and to determine the response rate and survival at the recommended phase II dose. PATIENTS AND METHODS: This study enrolled patients between December 1991 and August 1993. Eligibility criteria included histologically or cytologically documented stage III or IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 20 mg/m2) on days 1 and 6, cisplatin 100 mg/m2 on day 2, and 5-fluorouracil as a continuous infusion at 800 mg/m2/day for 4 days (days 2-5) with leucovorin 100 mg orally every 4 hours on days 1 through 5. Cycles were repeated every 21 days. RESULTS: Forty patients were treated during the study. The median age of the patients was 58 (range, 33-75) and 36 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in both patients treated with vinorelbine at 25 mg/m2. At the recommended phase II vinorelbine dose of 20 mg/m2 on days 1 and 6, myelosuppression remained the most common toxicity, with 22 patients (55%) having grade 4 neutropenia. Fifteen patients (38%) required hospital admission for neutropenic fever; two died of neutropenic sepsis. Of 33 patients evaluated, 2 patients achieved a complete response and 10 patients achieved a partial response (overall response rate, 30%; 36% of the evaluated patients). Median survival was 10.4 months for the entire cohort (16.4 months for those with stage III disease and 9.6 months for patients with stage IV disease) and 1-year survival was 45%. The overall median time to progression was 8.1 months. CONCLUSIONS: The maximum tolerated dose of vinorelbine given on days 1 and 6 with PFL is 20 mg/m2; myelosuppression is the dose-limited factor. The response rate is similar to rates observed in prior studies of combination chemotherapy, but the median survival of patients with stage IV disease exceeds that of many other regimens.