A community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy.

BACKGROUND: Pharmacokinetically guided (PK-guided) versus body surface area-based 5-fluorouracil (5-FU) dosing results in higher response rates and better tolerability. A paucity of data exists on PK-guided 5-FU dosing in the community setting. PATIENTS AND METHODS: Seventy colorectal cancer patients, from one academic and five community cancer centers, received the mFOLFOX6 regimen (5-FU 2,400 mg/m(2) over 46 hours every 2 weeks) with or without bevacizumab at cycle 1. The 5-FU continuous-infusion dose was adjusted for cycles 2-4 using a PK-guided algorithm to achieve a literature-based target area under the concentration-time curve (AUC). The primary objective was to demonstrate that PK-guided 5-FU dosing improves the ability to achieve a target AUC within four cycles of therapy. The secondary objective was to demonstrate reduced incidence of 5-FU-related toxicities. RESULTS: At cycles 1 and 4, 27.7% and 46.8% of patients achieved the target AUC (20-25 mg × hour/L), respectively (odds ratio [OR]: 2.20; p = .046). Significantly more patients were within range at cycle 4 compared with a literature rate of 20% (p < .0001). Patients had significantly higher odds of not being underdosed at cycle 4 versus cycle 1 (OR: 2.29; p = .037). The odds of a patient being within range increased by 30% at each subsequent cycle (OR: 1.30; p = .03). Less grade 3/4 mucositis and diarrhea were observed compared with historical data (1.9% vs 16% and 5.6% vs 12%, respectively); however, rates of grade 3/4 neutropenia were similar (33% vs 25%-50%). CONCLUSION: PK-guided 5-FU dosing resulted in significantly fewer underdosed patients and less gastrointestinal toxicity and allows for the application of personalized colorectal cancer therapy in the community setting.

The role of alpha(v)beta(3) in prostate cancer progression.

Integrin alpha(v)beta(3) is involved in varied cell biological activities, including angiogenesis, cell adhesion, and migration on several extracellular matrix components. Although alpha(v)beta(3) is not typically expressed in epithelial cells, it is expressed in macrophages, activated leukocytes, cytokine-stimulated endothelial cells, osteoclasts, and certain invasive tumors. Interestingly, the adhesion and migration of breast cancer cells on bone matrix are mediated, in part, by alpha(v)beta(3). Similar to breast cancer cells, prostate cancer cells preferentially metastasize to the bone. The biological events that mediate this metastatic pattern of prostate cancer are not well defined. This review discusses the role alpha(v)beta(3) plays in prostate cancer progression, with specific emphasis on bone metastasis and on alpha(v)beta(3) signaling in prostate cancer cells. The data suggest that alpha(v)beta(3), in part, facilitates prostate cancer metastasis to bone by mediating prostate cancer cell adhesion to and migration on osteopontin and vitronectin, which are common proteins in the bone microenvironment. These biological events require the activation of focal adhesion kinase and the subsequent activation of PI-3 kinase/Akt signaling pathway.

New discoveries in prostate cancer biology and treatment. 5-9 December 2001, Naples, Florida, USA.

Androgen independence and bone metastasis are lethal complications in patients with advanced prostate cancer. Presently, there is no cure for patients with androgen-independent prostate cancer. In order to develop more effective therapies for this disease, the molecular events involved in the development of androgen independence and bone metastasis must be elucidated and then targeted by therapeutic agents. Several studies presented at a recent conference on prostate cancer sponsored by the American Association for Cancer Research (AACR) provided evidence that prostate cancer metastasis to bone is mediated by the prostate cancer cell expression of molecules that allow the cells to invade, grow in and stimulate cells in the bone microenvironment resulting in an osteoblastic reaction. Androgen independence was reportedly mediated by an increased expression of survival genes following androgen ablation therapies and several molecular mechanisms involved in genetic instability. Treatment strategies are being designed to target some of the molecular events involved in androgen independence and bone metastasis. Targeting these molecular events with combinational therapies will hopefully delay the progression to androgen independence in patients with early stage disease, suppress the growth of androgen-independent cells in patients with advanced disease and enhance the chemosensitivity of androgen-independent cells.

Antimetastatic drugs in prostate cancer.

Despite the benefits of local therapy with radical prostatectomy and radiation, many patients with prostate cancer require hormonal ablation. While chemotherapy has proven efficacy when the disease progresses to androgen-independent prostate cancer, patients ultimately succumb to the disease, thus the identification of other active therapies is needed. Future treatment modalities include molecular targeted therapies. Prostate cancer has been an ideal model to study the multiple steps required in the metastatic cascade. These steps have been utilized in the development of metastasis inhibitors. This review will present promising agents that have been tested preclinically or are undergoing clinical investigation for their abilities in preventing prostate cancer metastasis. Because prostate cancer metastasizes preferentially to the bone, special attention will be given to agents that interfere with this pattern of metastasis. Specifically, the efficacy of angiogenesis inhibitors, metalloproteinase inhibitors, inhibitors of prostate cancer cell- endothelial cell interactions, and bisphosphonates will be reported. In addition, the introduction of these novel agents has raised many questions as to the relevance and optimal utilization of current clinical trial designs. Issues regarding combination therapy with chemotherapy, optimal timing of treatment with metastatic inhibitors, and the need for surrogate endpoints for molecular targeted therapies will be discussed.

Phase II trial of paclitaxel, estramustine, etoposide, and carboplatin in the treatment of patients with hormone-refractory prostate carcinoma.

BACKGROUND: Preclinical data suggest that the combination of intravenous (i.v.) paclitaxel, carboplatin, oral etoposide, and oral estramustine (TEEC) has significant activity in patients with advanced, hormone-refractory prostate carcinoma. The authors conducted this clinical trial to evaluate the addition of carboplatin to the three-drug combination of paclitaxel, estramustine, and etoposide (TEE). METHODS: Twenty patients with carcinoma of the prostate that was progressing despite hormone therapy were enrolled on this Phase II trial. Patients were treated with oral estramustine, 280 mg three times daily, and oral etoposide, 50 mg/m2, once daily on Days 1-7, with i.v. paclitaxel, 135 mg/m2, over 1 hour followed by carboplatin (area under the curve, 5) on Day 2 of each 21-day treatment cycle. Patients were evaluated for response after three cycles, and three additional cycles were given to responding or stable patients. RESULTS: Nineteen patients were evaluable for response, and 12 patients had measurable disease at baseline. The measurable response rate was 58% (7 of 12 patients; 95% confidence interval [95% CI], 28-85%), and all of those were partial responses. Eleven patients had decreases >50% from their baseline prostate specific antigen levels during therapy, for a response rate of 58% (95% CI, 34-80%) by this criterion. The median time to disease progression was 5.5 months, with a median survival of 14.2 months. Major toxicities included Grade (according to version 2 of the National Cancer Institute Common Toxicity Criteria) 4 neutropenia in 4 patients, Grade 4 thrombocytopenia in 4 patients, and anemia > or = Grade 3 in 4 patients. One patient had a deep vein thrombosis. CONCLUSIONS: The combination of TEEC was active in patients with hormone-refractory prostate carcinoma. The regimen was tolerable, with primarily hematologic toxicity. The addition of carboplatin to TEE did not appear to add to the efficacy of the three-drug combination of antimicrotubule agents.

A functional thrombin receptor (PAR1) is expressed on bone-derived prostate cancer cell lines.

OBJECTIVES: To identify genes important in prostate cancer metastatic to bone. Bone-specific metastasis is a common feature of prostate cancer and a significant cause of morbidity. METHODS: To identify factors involved in organ-specific metastasis, we used cDNA microarray analysis to compare a bone-derived cell line, VCaP, with a soft tissue-derived cell line, DuCaP. Both cell lines were derived from the same patient and spontaneously passaged. RESULTS: Forty-five genes were differentially expressed, and only seven of these also had increased expression in VCaP compared with normal prostatic tissue. Of these, protease-activated receptor 1 (PAR1) was verified as having increased expression by reverse transcriptase-polymerase chain reaction and Northern blot analysis, as well as by immunohistochemistry. PAR1 expression in a panel of prostate cancer cell lines demonstrated increased expression in those cell lines derived from bone metastases. Alpha-thrombin stimulation of the VCaP cells produced a dose-dependent mobilization of intracellular calcium compared with DuCaP, suggesting that PAR1 expressed on the VCaP prostate cancer cell line is functional. CONCLUSIONS: These data indicate that a functional PAR1 is expressed on prostate cancer cell lines. The prostate cancer cell lines expressing PAR1 appear to have an association with increased bone metastases.

Stromal factors involved in prostate carcinoma metastasis to bone.

BACKGROUND: Prostate carcinoma (PC) frequently metastasizes to bone, where it causes significant morbidity and mortality. Stromal elements in the primary and metastatic target organs are important mediators of tumor cell intravasation, chemoattraction, adhesion to target organ microvascular endothelium, extravasation, and growth at the metastatic site. METHODS: The role of stromal factors in bone metastasis was determined with a cyclic DNA microarray comparison of a bone-derived cell PC cell line with a soft tissue-derived cell PC cell line and by evaluating the effects of selected stromal components on PC cell chemotaxis, cell adhesion to human bone marrow endothelium (HBME), and PC cell growth. RESULTS: The authors demonstrate that PC cells express protease-activated receptor 1 (PAR1; thrombin receptor), and its expression is up-regulated in PC compared with normal prostate tissue. In addition, this overexpression was very pronounced in bone-derived PC cell lines (VCaP and PC-3) compared with soft tissue PC cell lines (DUCaP, DU145, and LNCaP). The authors report that bone stromal factors, including stromal cell-derived factor 1 (SDF-1) and collagen Type I peptides, are chemoattractants for PC cells, and they demonstrate that some of these factors (e.g., extracellular matrix components, transforming growth factor beta, bone morphogenic proteins [BMPs], and SDF-1) significantly alter PC-HBME interaction in vitro. Finally, stromal factors, such as BMPs, can regulate the proliferation of PC cells in vitro. CONCLUSIONS: Soluble and insoluble elements of the stroma are involved in multiple steps of PC metastasis to bone. The authors hypothesize that PAR1 may play a central role in prostate tumorigenesis.