Integrating chemohormonal therapy and surgery in known or suspected lymph node metastatic prostate cancer.

BACKGROUND: Prostate cancer persisting in the primary site after systemic therapy may contribute to emergence of resistance and progression. We previously demonstrated molecular characteristics of lethal cancer in the prostatectomy specimens of patients presenting with lymph node metastasis after chemohormonal treatment. Here we report the post-treatment outcomes of these patients and assess whether a link exists between surgery and treatment-free/cancer-free survival. METHODS: Patients with either clinically detected lymph node metastasis or primaries at high risk for nodal dissemination were treated with androgen ablation and docetaxel. Those responding with PSA concentration <1 ng ml(-1) were recommended surgery 1 year from enrollment. ADT was withheld postoperatively. The rate of survival without biochemical progression 1 year after surgery was measured to screen for efficacy. RESULTS: Forty patients were enrolled and 39 were evaluable. Three patients (7.7%) declined surgery. Of the remaining 36, 4 patients experienced disease progression during treatment and 4 more did not reach PSA <1. Twenty-six patients (67%) completed surgery, and 13 (33%) were also progression-free 1 year postoperatively (8 with undetectable PSA). With a median follow-up of 61 months, time to treatment failure was 27 months in the patients undergoing surgery. The most frequent patterns of first disease recurrence were biochemical (10 patients) and systemic (5). CONCLUSIONS: Half of the patients undergoing surgery were off treatment and progression-free 1 year following completion of all therapy. These results suggest that integration of surgery is feasible and may be superior to systemic therapy alone for selected prostate cancer patients presenting with nodal metastasis.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Effect of Paget's disease of bone (osteitis deformans) on the progression of prostate cancer bone metastasis.

BACKGROUND: Patients with prostate cancer tend to die from bone metastases. Until now, no evidence has shown that Paget's disease of bone (PDB) affects the progression of bone metastasis or overall survival of patients with prostate cancer. METHODS: We searched our patient database for men who had presented with prostate cancer and PDB between June 1993 and March 2009, and identified best-matched control patients according to stage, grade, age, date of diagnosis, treatment, and race. RESULTS: Among 1346 consecutive patients with prostate cancer diagnosed before 2008, 15 were confirmed to have comorbid PDB. Twenty-six more were identified from the institutional billing search. Including the 41 best-matched controls, our total study population was 82 patients. In the Kaplan-Meier analysis, we estimated median times from diagnosis of prostate cancer to bone metastasis to be 21.5 years for those with PDB and 9.4 years for those without PDB (P=0.044). Median overall survival times were 11.8 and 9.2 years for the two groups, respectively (P=0.008). CONCLUSION: For the first time, we have obtained evidence that patients with prostate cancer and PDB have delayed time to bone metastases and improved overall survival than do patients with prostate cancer alone.

A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: We investigated cytokines and angiogenic factors (CAFs) in patients with metastatic renal cell carcinoma (mRCC) treated in a randomized phase II clinical trial of sorafenib versus sorafenib+ interferon-α (IFN-α) that yielded no differences in progression-free survival (PFS). We aimed to link the CAF profile to PFS and select candidate predictive and prognostic markers for further study. METHODS: The concentrations of 52 plasma CAFs were measured pretreatment (n = 69), day 28, and day 56 using multiplex bead arrays and enzyme-linked immunosorbent assay. We investigated the association between baseline levels of CAFs with PFS and posttreatment changes. RESULTS: Unsupervised CAF clustering analysis revealed two distinct mRCC patient groups with elevated proangiogenic or proinflammatory mediators. A six-marker baseline CAF signature [osteopontin, vascular endothelial growth factor (VEGF), carbonic anhydrase 9, collagen IV, VEGF receptor-2, and tumor necrosis factor-related apoptosis-inducing ligand] correlated with PFS benefit (hazard ratio 0.20 versus 2.25, signature negative versus positive, respectively; P = 0.0002). While changes in angiogenic factors were frequently attenuated by the sorafenib+ IFN combination, most key immunomodulatory mediators increased. CONCLUSIONS: Using CAF profiling, we identified two mRCC patient groups, a candidate plasma signature for predicting PFS benefit, and distinct marker changes occurring with each treatment. This platform may provide valuable insights into renal cell carcinoma biology and the molecular consequences of targeted therapies.

Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial.

BACKGROUND: This phase 1/2 study assessed sunitinib combined with docetaxel (Taxotere) and prednisone in chemotherapy-naive metastatic, castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: To determine the recommended phase 2 dose (RP2D), 25 patients in four dose escalation cohorts received 3-week cycles of sunitinib (2 weeks on, 1 week off), docetaxel and prednisone, preceded by a 4-week sunitinib 50 mg/day lead in. RP2D was evaluated in 55 additional patients. The primary end point was prostate-specific antigen (PSA) response rate. RESULTS: One phase 1 dose-limiting toxicity occurred (grade 3 hyponatremia). The RP2D was sunitinib 37.5 mg/day, docetaxel 75 mg/m(2) and prednisone 5 mg b.i.d. During phase 2, confirmed PSA responses occurred in 31 patients [56.4% (95% confidence interval 42.3-69.7)]. Median time to PSA progression was 9.8 months. Forty-one patients (75%) were treated >3 months, 12 (22%) completed the study (16 cycles) and 43 (78%) discontinued (36% for disease progression and 27% adverse events). The most frequent treatment-related grade 3/4 adverse events were neutropenia (53%; 15% febrile) and fatigue/asthenia (16%). Among 33 assessable patients, 14 (42.4%) had confirmed partial response. Median progression-free and overall survivals were 12.6 and 21.7 months, respectively. CONCLUSION: This combination was moderately well tolerated, with promising response rate and survival benefit, justifying further investigation in mCRPC.

Usefulness of the top-scoring pairs of genes for prediction of prostate cancer progression.

Prediction of cancer progression after radical prostatectomy is one of the most challenging problems in the management of prostate cancer. Gene-expression profiling is widely used to identify genes associated with such progression. Usually candidate genes are identified according to a gene-by-gene comparison of expression. Recent reports suggested that relative expression of a gene pair more efficiently predicts cancer progression than single-gene analysis does. The top-scoring pair (TSP) algorithm classifies phenotypes according to the relative expression of a pair of genes. We applied the TSP approach to predict, which patients would experience systemic tumor progression after radical prostatectomy. Relative expression of TPD52L2/SQLE and CEACAM1/BRCA1 gene pairs identified those patients with more than 99% specificity but relatively low sensitivity (approximately 10%). These two gene pairs were validated in three independent data sets. In addition, combining two pairs of genes improved sensitivity without compromising specificity. Functional annotation of the TSP genes showed that they cluster by a limited number of biological functions and pathways, suggesting that relatively lower expression of genes from specific pathways can predict cancer progression. In conclusion, comparative analysis of the expression of two genes may be a simple and effective classifier for prediction of prostate cancer progression. In summary, the TSP approach can be used to identify patients whose prostate cancer will progress after they undergo radical prostatectomy. Two gene pairs can predict which men would experience progression to the metastatic form of the disease. However, because our analysis was based on a relatively small number of genes, a larger study will be needed to identify the best predictors of disease outcome overall.

The role of caveolin-1 in prostate cancer: clinical implications.

Caveolin-1 (cav-1) is reportedly overexpressed in prostate cancer cells and is associated with disease progression. Specific oncogenic activities of cav-1 associated with Akt activation also occur in prostate cancer. A membrane-associated protein, cav-1, is nonetheless secreted by prostate cancer cells; results of recent studies showed that secreted cav-1 can stimulate cell survival and angiogenic activities, defining a role for cav-1 in the prostate cancer microenvironment. Serum cav-1 levels were also higher in prostate cancer patients than in control men without prostate cancer, and the preoperative serum cav-1 concentration had prognostic potential in men undergoing radical prostatectomy. Secreted cav-1 is therefore a potential biomarker and therapeutic target for prostate cancer.

Dynamic change in phosphorylated platelet-derived growth factor receptor in peripheral blood leukocytes following docetaxel therapy predicts progression-free and overall survival in prostate cancer.

In a placebo-controlled randomised study of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate and docetaxel in metastatic prostate cancer with bone metastases (n=116), no significant differences in progression-free and overall survival were observed. To evaluate pharmacodynamic correlates of outcomes, we assessed the association of plasma platelet-derived growth factor (PDGF) isoform kinetics and PDGFR inhibition with progression-free and overall survival by individual treatment arm. We found that in the docetaxel-placebo arm alone, the probability of decrease in PDGFR phosphorylation (Pr-Decr-pPDGFR) above 0.5 (vs 30 months (HR 3.1; P=0.04 in log-rank test). By contrast, in the docetaxel plus imatinib arm, the association of Pr-Decr-pPDGFR >0.5 with a rise in plasma PDGF isoform concentrations and inferior survival was not observed. The data suggest that dynamic changes in PDGFR phosphorylation in peripheral blood leukocytes predict docetaxel efficacy. Rising plasma PDGF concentrations may explain and/or mark docetaxel resistance. Validation and mechanistic studies addressing these unexpected findings should anticipate a confounding influence of concurrent PDGFR inhibitor therapy.

A 45-kDa ErbB3 secreted by prostate cancer cells promotes bone formation.

ErbB3 is a transmembrane growth factor receptor that has been implicated in the pathogenesis of human cancer. After finding that a truncated form of ErbB3 was present and upregulated in metastatic prostate cancer cells in lymph nodes and bone, we explored the pathophysiological functions of this unusual form of ErbB3 in the context of mouse calvaria as well as osteoblasts in vitro and the femur microenvironment in vivo. Here we demonstrate that prostate cancer cells expressed an alternatively spliced transcript that encodes a 45-kDa glycosylated protein (p45-sErbB3). The recombinant p45-sErbB3 purified from conditioned medium stimulated calvarial bone formation and induced osteoblast differentiation. Overexpression of p45-sErbB3 in the osteolytic prostate cancer cell line PC-3 converted its phenotype from bone lysing to bone forming upon injection into the femurs of immunodeficient mice. Further, we detected sErbB3 in plasma samples from patients with castration-resistant prostate cancer with bone metastasis. These observations establish that p45-sErbB3 is a structurally and functionally unique gene product of ErbB3 and suggest that p45-sErbB3 is likely one of the factors involved in the osteoblastic bone metastases of prostate cancer.

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone.

The tendency of prostate cancer to produce osteoblastic bone metastases suggests that cancer cells and osteoblasts interact in ways that contribute to cancer progression. To identify factors that mediate these interactions, we compared gene expression patterns between two bone-derived prostate cancer cell lines that produce osteoblastic (MDA PCa 2b) or osteolytic lesions (PC-3). Both cell lines expressed Wnt ligands, including WNT7b, a canonical Wnt implicated in osteogenesis. PC-3 cells expressed 50 times more Dickkopf-1 (DKK1), an inhibitor of Wnt pathways, than did MDA PCa 2b cells. Evaluation of the functional role of these factors (in cocultures of prostate cancer cells with primary mouse osteoblasts (PMOs) or in bone organ cultures) showed that MDA PCa 2b cells activated Wnt canonical signaling in PMOs and that DKK1 blocked osteoblast proliferation and new bone formation induced by MDA PCa 2b cells. MDA PCa 2b cells did not induce bone formation in calvaria from mice lacking the Wnt co-receptor Lrp5. In human specimens, WNT7b was not expressed in normal prostate but was expressed in areas of high-grade prostate intraepithelial neoplasia, in three of nine primary prostate tumor specimens and in 16 of 38 samples of bone metastases from prostate cancer. DKK1 was not expressed in normal or cancerous tissue but was expressed in two of three specimens of osteolytic bone metastases (P=0.0119). We conclude that MDA PCa 2b induces new bone formation through Wnt canonical signaling, that LRP5 mediates this effect, and that DKK1 is involved in the balance between bone formation and resorption that determines lesion phenotype.

15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor gamma.

An inverse relationship exists between the expression of 15-lipoxygenase-2 (15-LOX-2) and peroxisome proliferator-activated receptor gamma (PPARgamma) in normal prostate epithelial cells (PrECs) compared with their expression in prostate carcinoma cells (PC-3). The reason for this difference, however, is unknown. We hypothesized that this inverse expression partly involves the 15-LOX-2 promoter and 15-S-hydroxyeicosatetraenoic acid (15-(S)-HETE), a product of 15-LOX-2 that binds to PPARgamma. We identified an active steroid nuclear receptor half-site present in the 15-LOX-2 promoter fragment F-5 (-618/+177) that can interact with PPARgamma. After forced expression of wild-type PPARgamma, 15-(S)-HETE (1 microM) decreased F-5 reporter activity in PrECs whereas forced expression of 15-LOX-2 resulted in 15-(S)-HETE production which enhanced F-5 activity in PC-3. In contrast, the expression of dominant-negative PPARgamma reversed the transcriptional activation of F-5 by enhancing it 202-fold in PrEC or suppressing it in PC-3; the effect in PC-3 was positively increased 150-fold in the presence of 15-(S)-HETE (1 microM). Peroxisome proliferator-activated receptor gamma interacted with 15-LOX-2 promoter sequences in pulldown experiments using biotinylated 15-LOX-2 (-560/-596 bp) oligonucleotides. In gelshift analyses PPARgamma and orphan receptor RORalpha were shown to interact with the F-5 fragment in PC-3 cells. These data suggest that crosstalk mechanisms exist between the 15-LOX-2 gene and PPARgamma to counterbalance expression and help explain the inverse relationship of these genes in normal versus cancer cells.

Alternating dose-dense chemotherapy in patients with high volume disseminated non-seminomatous germ cell tumours.

Only about half of patients with a poor-prognosis non-seminomatous germ-cell tumours can achieve a cure. The aim of this phase II study was to assess the efficacy and toxicity of a dose-dense alternating chemotherapy regimen in this subset of patients. High volume non-seminomatous germ-cell tumours was defined as follows: at least two sites of non pulmonary metastases, an extragonadal primary tumour, a serum human chorionic gonadotropin level higher than 10 000 mIU x ml(-1), or a alpha-foetoprotein level higher than 2000 mIU ml(-1). Patients who fulfilled these criteria were treated with the so-called BOP-CISCA-POMB-ACE regimen (bleomycin, vincristine, and cisplatin; cisplatin, cyclophosphamide, and doxorubicin; cisplatin, vincristine, methotrexate, and bleomycin; etoposide, dactinomycin, and cyclophosphamide) plus granulocyte colony-stimulating factor. A total of 58 patients were enrolled. Patients were retrospectively classified according to the International Germ-Cell Cancer Consensus Group classification; 38 patients (66%) had poor-prognosis disease and 19 patients (33%) had intermediate-prognosis. Patients received a median of 2.5 courses (range 0.25 to five courses) of the BOP-CISCA-POMB-ACE regimen. Forty-two patients (72.4%) had a complete response to therapy. With a median follow-up time of 31 months, the 3-year progression-free survival rate was 71% (95% confidence interval, 60 to 84%) and the 3-year overall survival rate was 73% (95% confidence interval: 62 to 86%). The 3-year PFS rates were 83% (95% confidence interval: 68 to 100%) in the intermediate-prognosis group and 65% (95% confidence interval: 51 to 82%) in the poor-prognosis group. Early side effects included mainly grade 4 haematologic toxicity (neutropaenia in 79% of patients, thrombocytopaenia in 69%, anaemia in 22%), grade 4 stomatitis (19%), and four early deaths (7% of patients), at least partially related to toxicity. The dose-dense BOP-CISCA-POMB-ACE regimen is highly active in patients with non-seminomatous germ-cell tumours classified as intermediate-prognosis or poor-prognosis according to the International Germ-Cell Cancer Consensus Group. Because outcomes with this regimen compare favourably with outcome after standard therapy, dose-dense chemotherapy should be further investigated in this subset of patients.

A 20% dose reduction of the original CISCA/VB regimen allows better tolerance and similar survival rate in disseminated testicular non-seminomatous germ-cell tumors: final results of a phase III randomized trial.

BACKGROUND: This prospective randomized clinical trial was designed to compare the efficacy of a low-dose regimen of cisplatin, doxorubicin and cyclophosphamide alternated with vinblastine and bleomycin (CISCA/VB) with the original CISCA/VB regimen in patients with disseminated nonseminomatous germ-cell tumors (NSGCT) and a predicted favorable outcome. PATIENTS AND METHODS: One hundred and twenty-five patients with disseminated NSGCT and a predicted favorable outcome according to the M.D. Anderson Cancer Center classification [testicular primary and human chorionic gonadotropin (hCG) serum level <50000 mIU/ml] were randomized to receive the original CISCA/VB regimen (100% dose) or a low-dose CISCA/VB regimen (80% dose). RESULTS: Among the 124 eligible patients, there was no significant difference in the number of patients in the two treatment arms who achieved a complete response to therapy: 53 of 65 patients (82%) on the original CISCA/VB regimen and 53 of 59 patients (90%) on the low-dose CISCA/VB regimen (P = 0.29). Overall, the original CISCA/VB regimen resulted in a significantly higher relative dose intensity (P <0.0001). After a median follow-up of 6.8 years (range 0.37 to 12.94 years), there was no significant difference in disease-free survival (P = 0.87) or in overall survival (P = 0.88) between the two treatment arms. The 5-year overall survival rate was 93.7% [95% confidence interval (CI) 88% to 100%] and 94.1% (95% CI 84% to 100%) in the original CISCA/VB arm and the low-dose CISCA/VB arm, respectively. The 5-year overall survival rate for the entire study population was 98% (95% CI 94% to 100%) and 88% (95% CI 76% to 100%) in the good- and intermediate-prognosis groups, respectively, as defined by the International Germ Cell Consensus Classification Group (IGCCCG). The low-dose CISCA/VB regimen resulted in significantly less neutropenic fever (P <0.001), grade 4 thrombocytopenia (P <0.03) and severe mucositis (P <0.01) than the original CISCA/VB regimen. CONCLUSIONS: CISCA/VB is highly efficient in patients with good or intermediate prognosis NSGCT according to the IGCCCG criteria. Although equivalent antitumor efficacy cannot be claimed, the low-dose CISCA/VB regimen appears to be a better mode of delivery than the original CISCA/VB regimen with respect to toxicity, since survival is comparable.

Germ cell tumors in patients infected by the human immunodeficiency virus.

BACKGROUND: The objective of this study was to assess the natural history of the two disease courses, patient immune system tolerance, and results of therapy in human immunodeficiency virus (HIV)-infected patients with germ cell tumors (GCT). METHODS: From 1985 to 1996, 34 HIV-infected men received a diagnosis of GCT. Their charts were analyzed retrospectively. RESULTS: Sixteen patients had seminomas, and 18 had nonseminomatous GCTs (NSGCT); 71% had International Union Against Cancer (UICC), 1997 Stage I-II GCTs. At the time of chemotherapy, 69%, 6%, and 25% of patients with advanced NSGCT were in the International Germ Cell Consensus Classification (IGCCC) good, intermediate, and poor prognostic group, respectively. All except 1 of the 10 patients with advanced seminomas were in the IGCCC good prognostic group. At diagnosis of GCT, 85% of patients were classified as having asymptomatic HIV infection or only persistent generalized lymphadenectomy. The median CD4 cell count was 325/microL (range, 6-1125). Overall, 26 patients were given chemotherapy, but the planned dose intensity was respected in only 15 (57%) patients. Severe toxic effects included febrile neutropenia in 35% of patients. During chemotherapy, zidovudine, prophylactic granulocyte colony-stimulating factor (G-CSF), and a Pneumocystis carinii prophylaxis were given in 19%, 23%, and 35% of cases, respectively. CD4 cell count decreased in 7 (64%) of 11 patients during chemotherapy. Infradiaphragmatic radiotherapy was given in 10 cases and was clinically well tolerated. At a median follow-up of 27 months (range, 3-150), 50% of patients were alive, and only 18% of patients died of GCT. Two patients developed a non-GCT malignancy while in complete remission, namely, Hodgkin disease and an acute leukemia. CONCLUSIONS: The prognosis of GCT in HIV-infected patients is mostly dictated by the HIV infection. Patients should be treated according to stage and histologic subtype, although dose reduction of chemotherapy might be necessary in approximately half of the patients. Close surveillance of neutrophil and CD4 cells counts, as well as the use of G-CSF and systematic anti-Pneumocystis carinii prophylaxis are recommended during chemotherapy. The use of highly active antiretroviral therapy during chemotherapy for GCT requires a prospective assessment.

Clinical evaluation of adenoviral-mediated p53 gene transfer: review of INGN 201 studies.

Gene therapy represents a new modality of cancer therapeutics based on novel mechanisms of action. Modified adenoviruses have important properties that lend themselves readily to commercial-scale manufacturing; with an excellent safety record, they have been used as the gene transfer vector in most clinical studies to date. They provide a potent means of delivering genes into cancer cells. Although multiple genes are involved in the development of malignancy, preclinical models (and now clinical studies) have proven that insertion of a single gene, p53, can arrest cancer cell growth and induce apoptosis and tumor regression in advanced cancers such as squamous cell cancer of the head and neck and non-small cell lung cancer. With equally strong rationale, clinical studies using combination approaches also have been initiated, with promising results in localized inoperable non-small cell lung cancer. In addition, the apparent safety, and especially the lack of adverse effects on normal tissues at injection sites following gene transfer, have stimulated an evaluation of intervention in the postoperative surgical adjuvant setting and in treating premalignancies. The goal of these studies has been to provide an antitumor locoregional effect. This may result in effective palliation in the advanced-disease setting, especially for diseases that do not metastasize widely. However, the most exciting near-term potential of p53 gene transfer using INGN 201 will be in up-front regimens in combination with surgery, radiation, and chemotherapy in the many clinical settings where local disease control remains suboptimal.

Antitumor efficacy of 26-fluoroepothilone B against human prostate cancer xenografts.

BACKGROUND: Epothilone compounds (e.g. epothilones A and B) represent a new structural class of microtubule inhibitors with the remarkable ability to inhibit tumor growth of multidrug-resistant cell lines at low nanomolar or even subnanomolar concentrations. Unfortunately, this therapeutic efficacy has only been achieved to date with a narrow therapeutic window. Hence, other structural analogs of compounds such as epothilone B are currently being synthesized in the hope that they will demonstrate equivalent antitumor efficacy with reduced systemic toxicity. PURPOSE: To evaluate the relative efficacy and toxicity of selectively modified epothilone compounds. METHODS: Compounds were initially screened for relative cytotoxicity against the human prostate cancer cell lines PC3, LNCaP, MDA PCa 2a and MDA PCa 2b. Growth inhibitory IC50 values of 0.5 to 4 nM were obtained. From this initial screen, one epothilone compound, 26-fluoroepothilone B, was chosen for further evaluation against the growth of s.c.-implanted MDA PCa 2b- and PC3-derived prostate tumors in athymic nude mice. The compound was administered intravenously at 2, 5 and 10 mg/kg after the tumors had reached 300 mm3. Two control groups were used: paclitaxel (40 mg/kg) and saline. RESULTS: Following treatment with 10 mg 26-fluoroepothilone B/kg, there was a sustained decrease in tumor size for 30 days reaching a maximal reduction of 80% when compared with tumor growth in the saline control group. Sustained suppression (> 20 days) of tumor growth was observed following the second drug injection. Although a maximal body weight loss of 30% occurred after the second injection, all mice completely regained their initial body weight in 20 days. A lower dose (2 mg/kg) produced a 58% maximal reduction in tumor size and a 20% body weight loss. Minimal inhibition of tumor growth, however, was obtained with paclitaxel at a maximally tolerated dose (40 mg/kg). Other epothilones tested were either less effective and/or more toxic than 26-fluoroepothilone B. This new fluorinated epothilone compound supports the growth of paclitaxel-dependent Tax-18 mutant CHO cells and produces microtubule bundles similar to those produced by paclitaxel, indicating that the two drugs share a similar mechanism of action. CONCLUSION: A new fluorinated epothilone compound, 26-fluoroepothilone B, has been described that stabilizes microtubule structures based on its support of growth of a mutant paclitaxel-dependent CHO cell line. Its antitumor activity against human prostate cancer in nude mice is superior to that of paclitaxel at equivalent toxic doses. Further research is required to determine optimal dosing strategies and to fully assess the compound's activity against other malignant diseases.

Gemcitabine modulation of alkylator therapy: a phase I trial of escalating gemcitabine added to fixed doses of ifosfamide and doxorubicin.

BACKGROUND: The authors investigated the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) associated with the addition of a biomodulating dose of gemcitabine to an established regimen of ifosfamide and doxorubicin as part of a program to explore the potential of low-dose gemcitabine to modulate the activity of alkylating agents. METHODS: A Phase I trial was carried out in a population of patients with bladder or pelvic carcinoma for whom no standard therapy was available. Doses of ifosfamide and doxorubicin were held fixed at 2 g/m(2) for 4 days and 20 mg/m(2) for 3 days, respectively. Gemcitabine was given on Day 2 and Day 4 at doses of 90 mg/m(2), 150 mg/m(2), and 200 mg/m(2) per dose. RESULTS: A total of 18 patients received 53 courses of therapy. Myelosuppression was dose limiting. Nonhematologic toxicity also was significant, with 10 of 18 patients experiencing toxicity of Grade 3 or greater. For previously untreated patients with an intact performance status, the MTD for gemcitabine in this context was at least 150 mg/m(2) per dose. According to an intent-to-treat analysis, 11 of 18 patients demonstrated a clinically significant response to this regimen. CONCLUSIONS: The regimen of ifosfamide and doxorubicin with the addition of gemcitabine was significantly toxic but has promising activity. Based on the observed activity and the generally reversible nature of the toxicity, the authors have initiated a Phase II trial of this regimen in patients with untreated, metastatic urothelial carcinoma.