Biomedical subjects

Nancy A Dawson

Publications and source records attributed to Nancy A Dawson.

12 recordsLinked to original sources

PubMed2006

New molecular targets in advanced prostate cancer.

Classically, advanced prostate cancer has been treated with hormonal therapy and, most recently, chemotherapy. This treatment clearly demonstrated a survival benefit, but never a cure. With the ever-expanding understanding of the pathophysiology of prostate cancer, there has been a recent explosion in the potential molecular targets and novel therapeutic approaches to both advanced and potentially localized prostate cancer. This review will focus on what the author perceives to be the most promising of these new strategies. The endothelin pathway has been identified as pivotal in the viscous cycle of tumorigenesis in bone, leading to the development of endothelial receptor antagonists. Vaccine therapy using autologous granulocyte-macrophage colony-stimulating factor-producing prostate cancer cells has been effective in producing both immune and clinical responses. Randomized clinical trials of the immunotherapy cell product APC8015 (Provenge) have demonstrated improved survival in the hormone-refractory setting. The development of antisense oligonucleotides to segments of mRNA critical to the progression to androgen-independent disease has emerged as one further tool in the expanding armamentarium of potential therapies being tested. Clearly, headway is being made in improving outcomes in this most prevalent health problem.

Antineoplastic Agents↗

PubMed2004

A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma.

PURPOSE: The epidermal growth factor receptor (EGFR) is overexpressed in 75 to 90% of renal cell carcinomas and may play a role in tumor initiation and progression. Gefitinib (Iressa, ZD1839) is a potent, selective EGFR-tyrosine kinase inhibitor. This trial was undertaken to assess the efficacy and toxicity of gefitinib in advanced renal cell carcinoma. EXPERIMENTAL DESIGN: Oral gefitinib, 500 mg once daily, was given continuously. A single-dose reduction to 250 mg daily was allowed for toxicity. The primary end point was response rate (defined as complete remission + partial remission + stable disease). Secondary end points were progression-free survival, overall survival, toxicity, and correlation of response with EGFR status. RESULTS: Twenty-one patients were enrolled on this study, and all are evaluable for response and toxicity. Patient characteristics were median age 61 (range, 35-78 years); 17 males, 4 females; median performance status 0 (range 0-2); median number of prior systemic therapies 1 (range, 0-3). The median and mean number of cycles of therapy received was 3 and 4.7 (range, 1-14+). The best response was stable disease in eight patients (38%). Median progression-free survival was 2.7 months. Median overall survival was 8.3 months. The difference in overall survival was significantly different between patients with progressive disease versus stable disease (6.1 months versus 16+ months; Log-Rank test P value < 0.0001). Three patients required a dose reduction, all for grade 3 diarrhea. There was no apparent correlation between EGFR status and stability of disease or progression of disease. CONCLUSIONS: Gefitinib is without significant conventional activity in renal cell carcinoma. The relation of "stable disease" to treatment or to disease-related prognostic heterogeneity remains to be defined.

Adult↗

PubMed2004

Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583).

PURPOSE: Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of > or =50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy. PATIENTS AND METHODS: AiPCa patients were randomized to undergo AAWD alone (n=132), or together with K (400 mg orally [p.o.] tid) and hydrocortisone (30 mg p.o. each morning, 10 mg p.o. each evening; n=128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K. RESULTS: Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients who underwent AAWD and simultaneous K (P=.0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P=.02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response. Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at the time of disease progression. CONCLUSION: K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K and then climb at the time of progression, suggesting that progressive disease while on K may be due to tachyphylaxis to the adrenolytic properties of K.

Adenocarcinoma↗

PubMed2004

Platinum-free combination chemotherapy in patients with advanced or metastatic transitional cell carcinoma.

BACKGROUND: Platinum-based regimens have improved response rates and survival in patients with advanced transitional cell carcinoma (TCC) of the urothelial tract. However, the toxicities of platinum-based chemotherapy are considerable. Regimens with reduced toxicity that are applicable to a broader group of TCC patients without sacrificing activity therefore are of interest. METHODS: Because gemcitabine, paclitaxel, and methotrexate have each been reported to possess single-agent activity in this disease, the authors evaluated the tolerability and efficacy of fixed doses of paclitaxel (100 mg/m(2) over 3 hours) and methotrexate (30 mg/m(2)) with escalating doses of gemcitabine (800-1000 mg/m(2)), all given on Days 1 and 8 every 21 days, in patients with previously untreated unresectable or metastatic TCC. RESULTS: Twenty-five patients were enrolled. Two patients were ineligible and were excluded from analysis. Because no dose-limiting toxicity occurred in the first 4 patients who were given gemcitabine at a dose of 800 mg/m(2), the gemcitabine dose was escalated to 1000 mg/m(2) in the next 21 patients. Of the 21 patients assessable for response, 6 had achieved a complete response (CR) and 6 had achieved a partial response, for an overall response rate of 57%. An additional patient was converted to a CR surgically. The median overall and progression-free survival times were 18 months and 9.2 months, respectively. Toxicity was predominantly neutropenia: Grade 3 in 9 patients (39%) and Grade 4 in 4 patients (17%) (according to the Southwest Oncology Group Toxicity Criteria, version 12/1994). One patient died of septic shock associated with febrile neutropenia after three cycles. CONCLUSIONS: The regimen of gemcitabine, paclitaxel, and methotrexate at this dose and schedule was found to possess activity in patients with locally advanced or metastatic TCC. Further studies of this regimen are warranted.

Adult↗

PubMed2004

Update on hormone-refractory prostate cancer.

PURPOSE OF REVIEW: Androgen deprivation therapy is the cornerstone treatment for men with de novo or recurrent metastatic prostate cancer. Unfortunately, androgen deprivation therapy is primarily palliative, with nearly all men progressing to an androgen-independent state. Hormone-refractory prostate cancer presents significant management challenges and is the focus of this review. RECENT FINDINGS: Investigations into the pathophysiology of hormone-refractory prostate cancer, the exploration of chemotherapeutic combinations, novel biological targets, skeletal protectants, and radiopharmaceuticals, as well as new prognostic tools are expanding the clinician's armamentarium and improving patient outcomes. SUMMARY: Bisphosphonates and chemotherapy are providing effective palliative approaches. Phase II trials of taxane-based regimens show higher response rates and longer survival than has typically been achieved with existing standards. Two completed randomized phase III studies to be reported in mid-2004 will more definitively answer the question of whether currently available chemotherapy can improve survival.

Androgen Antagonists↗

PubMed2003

Novel approaches to treat asymptomatic, hormone-naive patients with rising prostate-specific antigen after primary treatment for prostate cancer.

Biochemical-only recurrent prostate cancer presents the ideal setting for assessing novel agents or approaches for prostate cancer treatment. There is no clear evidence that delay in initiation of more definitive androgen-deprivation therapy is harmful, and a simple blood test--the prostate-specific antigen (PSA) level--is readily available to screen for potential antineoplastic activity. Current novel approaches include vaccines, cyclooxygenase-2 (COX-2) inhibitors, selective apoptotic antineoplastic drugs, endothelin-A receptor antagonists, chemotherapy, vitamin D, and peroxisome proliferator-activated receptor-gamma agonists. In this screening process, certain therapies have emerged as delaying PSA progression or decelerating PSA velocity. These therapies, such as the COX-2 inhibitors, will need to proceed to phase 3 trials to answer the more important question of whether this change in PSA dynamics translates into improved survival. Patients enrolling in these trials need to be clearly informed of the limited expectations of these novel exploratory approaches.

Adenocarcinoma↗

PubMed2003

Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer.

PURPOSE: To develop and validate a model that can be used to predict the overall survival probability among metastatic hormone-refractory prostate cancer patients (HRPC). PATIENTS AND METHODS: Data from six Cancer and Leukemia Group B protocols that enrolled 1,101 patients with metastatic hormone-refractory adenocarcinoma of the prostate during the study period from 1991 to 2001 were pooled. The proportional hazards model was used to develop a multivariable model on the basis of pretreatment factors and to construct a prognostic model. The area under the receiver operating characteristic curve (ROC) was calculated as a measure of predictive discrimination. Calibration of the model predictions was assessed by comparing the predicted probability with the actual survival probability. An independent data set was used to validate the fitted model. RESULTS: The final model included the following factors: lactate dehydrogenase, prostate-specific antigen, alkaline phosphatase, Gleason sum, Eastern Cooperative Oncology Group performance status, hemoglobin, and the presence of visceral disease. The area under the ROC curve was 0.68. Patients were classified into one of four risk groups. We observed a good agreement between the observed and predicted survival probabilities for the four risk groups. The observed median survival durations were 7.5 (95% confidence interval [CI], 6.2 to 10.9), 13.4 (95% CI, 9.7 to 26.3), 18.9 (95% CI, 16.2 to 26.3), and 27.2 (95% CI, 21.9 to 42.8) months for the first, second, third, and fourth risk groups, respectively. The corresponding median predicted survival times were 8.8, 13.4, 17.4, and 22.80 for the four risk groups. CONCLUSION: This model could be used to predict individual survival probabilities and to stratify metastatic HRPC patients in randomized phase III trials.

Adenocarcinoma↗

PubMed2003

Therapeutic benefit of bisphosphonates in the management of prostate cancer-related bone disease.

A diversity of bone pathology is present in men with prostate cancer. Androgen deprivation therapy (ADT) can cause significant and progressive osteopoenia and osteoporosis. Bone is also the primary site for metastases leading to associated pain, skeletal fractures and hypercalcaemia. Bisphosphonate therapy decreases bone resorption, which may prevent or reverse loss of bone mineral density. Both pamidronate and zoledronic acid have proven efficacy in preventing ADT-induced bone loss. In a randomised, placebo-controlled trial, in men with hormone-refractory prostate cancer, there was a decreased incidence of skeletal- related adverse events in men receiving zoledronic acid. So far, randomised trials have failed to show improved pain control. Formalised guidelines are needed to help clinicians decide which patients should be treated with bisphosphonates, when to initiate therapy and for what duration.

Androgens↗

PubMed2003

Point: It's never too soon.

A multidisciplinary approach to prostate cancer has become the rule and not the exception. Involving the entire team, which includes a medical oncologist, from the time of initial diagnosis is optimal. This facilitates maximal patient education regarding treatment options and enhances informed decision making. A coordinated approach also promotes enrollment on clinical trials, which are often, multimodality, especially in high-risk early stage prostate cancer. Integrated therapeutic strategies throughout the patient's disease course can improve both patient care and satisfaction

Humans↗

PubMed2002

Attitudes and use of complementary medicine in men with prostate cancer.

PURPOSE: Patients with cancer are increasingly incorporating complementary therapies into the overall treatment. We determine the prevalence and patterns of use of complementary therapies among patients with prostate cancer. MATERIALS AND METHODS: Patients attending 6 urology institutions for prostate cancer management completed a self-administered questionnaire on complementary therapy. All men diagnosed with prostate cancer were eligible, regardless of age, stage of disease or treatment. RESULTS: A total of 1,099 patients returned the questionnaire. The overall response rate was 78.5%. Complementary therapies had previously been or were currently being used by 23.5% (258) and 18.2% (200) of patients, respectively. Higher levels of education and income were associated with greater use of complementary therapy (p <0.002 by logistic regression). Patients with progressive disease or those primarily treated with hormones were most likely to use complementary therapy. Among the patients using complementary therapy 90% believed that it would help them live longer and improve quality of life, 60% believed it would relieve symptoms and 47% expected it to cure disease. CONCLUSIONS: Complementary therapies are used by a large number of patients with prostate cancer, particularly those with progressive disease or who have undergone multiple treatments. Health care providers need to recognize this growing pattern of use of complementary therapy. Among patients who use complementary therapy the perception of benefit is much greater than that supported by scientific data. Future research should aim to unravel the complex psychosocial dynamics that influence the decision to use complementary therapy by men with prostate cancer and to educate patients about the efficacy of such therapies.

Aged↗

PubMed2002

Bisphosphonates: their evolving role in the management of prostate cancer-related bone disease.

PURPOSE OF REVIEW: The use of androgen deprivation therapy has increased because of its use as part of multimodality therapy for high-risk early stage disease and in recurrent nonmetastatic disease. Hormonal therapy is associated with secondary osteoporosis and increased skeletal morbidity. Furthermore, in patients with established bone metastases, osseous complications are a significant problem. Bisphosphonates have been investigated in the prevention of bone density loss and skeletal morbidity. Results of these studies are now becoming available. RECENT FINDINGS: Data are emerging that demonstrate that bisphosphonates can prevent skeletal morbidity, such as pathologic fractures and spinal cord compression in men with hormone-refractory prostate cancer. The early use of bisphosphonates has also been shown to prevent bone loss due to androgen deprivation therapy. Current third-generation bisphosphonates are several hundred times more potent than their predecessors. Evidence is emerging that these drugs not only inhibit bone resorption but also are cytotoxic to prostate cancer cells. SUMMARY: Bisphosphonates are assuming a prominent ancillary role in prostate cancer therapy through their ability to prevent skeletal morbidity. Their potential to interfere with the formation of osseous tumor deposits has lead to investigations into the capacity of these drugs to prevent bone metastasis.

Bone Diseases↗

PubMed2002

Importance of serum hemoglobin in hormone refractory prostate cancer.

OBJECTIVES: In the search for an early measure of response in hormone refractory prostate cancer (HRPC), most have targeted changes in serum prostate-specific antigen (PSA). Up to this point, no one has targeted changes in serum hemoglobin during treatment. If dynamic changes in hemoglobin after treatment provide additive prognostic information to dynamic changes in PSA, then we should consider and test ways to incorporate serum hemoglobin into measures of response in HRPC. METHODS: Our patients consisted of 321 men who were studied on Cancer and Leukemia Group B protocols 9181 and 9182. We fit serial values of PSA and hemoglobin with an exponential model: y = exp(alpha + beta*t + gamma*t(2)) with y symbolizing either PSA or hemoglobin and t denoting time. We then used the Cox proportional hazard model to relate the parameters of the model (alpha, beta, and gamma) to subsequent survival. RESULTS: We found that the exponential model fit serial measurements of both PSA and serum hemoglobin well, and all three of the parameters for both markers related closely to subsequent survival (P < or = 0.003). The Cox model suggested a composite hazard score (HS) as a way to consolidate the information from serial measurements of both serum markers, and we observed that those with HS < 0 enjoyed a longer survival. CONCLUSION: Because serial measurements of serum hemoglobin during treatment of HRPC add prognostic information to serial measurements of PSA, we hypothesize that combining the dynamic changes in serum hemoglobin with those of PSA could lead to an improved measure of response in HRPC.

Hemoglobins↗