Biomedical subjects

Eric J Small

Publications and source records attributed to Eric J Small.

At least 19 recordsLinked to original sources

PubMed2007

The impact of prior radical prostatectomy in men with metastatic castration recurrent prostate cancer: a pooled analysis of 9 Cancer and Leukemia Group B Trials.

PURPOSE: A prior report suggested that radical prostatectomy may confer a survival advantage to patients with metastatic castration recurrent prostate cancer. Therefore, a pooled analysis of 9 trials performed by Cancer and Leukemia Group B was done to determine if men with metastatic castration recurrent prostate cancer who underwent prior prostatectomy had improved clinical outcomes, such as overall, prostate specific, progression-free and PSA progression-free survival, than men who did not undergo prior prostatectomy. MATERIALS AND METHODS: Data from 9 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive prostate cancer during androgen deprivation therapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic functions. The proportional hazards model was used to assess the prognostic importance of radical prostatectomy for predicting clinical outcomes. RESULTS: Of 1,238 men 310 (25%) underwent prostatectomy. Median survival was 14.7 (95% CI 12.9-16.7) and 14.5 months (95% CI 13.5-15.7) in men who did and did not undergo prostatectomy, respectively. The HR for death was 1.03 (95% CI 0.90-1.19, p = 0.65) in men with vs without prostatectomy. CONCLUSIONS: Prior prostatectomy in men with metastatic castration recurrent prostate cancer who were subsequently enrolled on clinical trials for cancer treatment had similar survival compared to men who did not undergo prior prostatectomy. These data do not support another report suggesting that prior prostatectomy confers a subsequent survival advantage in men with castration recurrent prostate cancer.

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PubMed2006

Intermittent chemotherapy for metastatic hormone refractory prostate cancer.

While docetaxel/prednisone chemotherapy has demonstrated a survival advantage in metastatic hormone refractory prostate cancer (HRPC) patients, the optimal duration of chemotherapy has not yet been established. Currently, a standard practice is to treat patients indefinitely until unacceptable toxicity or disease progression. A systematic approach to providing breaks in treatment schedules (intermittent chemotherapy) for patients who experience an initial response to chemotherapy may avoid or delay the development of progressive toxicity. Whether continuous therapy offers an advantage over intermittent therapy, in terms of balancing disease control and overall survival with treatment-related toxicities and quality-of-life (QOL) is yet unanswered. This article will: (1) review the data from prior studies of intermittent versus continuous chemotherapy in other solid tumors, (2) review existing trials of intermittent chemotherapy in prostate cancer, (3) discuss intermittent chemotherapy clinical trial design considerations, and (4) discuss the future role of intermittent chemotherapy for the treatment of prostate cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Telephone monitoring of distress in patients aged 65 years or older with advanced stage cancer: a cancer and leukemia group B study.

BACKGROUND: Significant barriers to cancer patients receiving mental health treatment for distress have been reported in the literature. The objective of the current study was to determine whether distress in older patients (aged 65 years and older) would be reduced with educational materials (EM) supplemented by monthly telephone monitoring (TM) (TM + EM) compared with the use of EM alone because of more timely referrals to appropriate health professionals. METHODS: One hundred ninety-two older patients with breast, prostate, and colorectal cancers who had advanced disease and currently were receiving treatment were randomized to receive either TM + EM or EM alone. One hundred thirty-one patients were evaluated by telephone interview for psychologic and physical distress and for social support at baseline and at 6 months using the Hospital Anxiety and Depression Scale (HADS), the European Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 quality-of-life questionnaire, and the Medical Outcomes Study (MOS) Social Support Survey. Patients who in the TM + EM group were called monthly for 6 months to monitor their distress using the HADS and EORTC physical symptom items and the MOS Social Support Survey items, with cutoff levels were established to indicate which patients were in greater distress. Those patients who scored above the cutoff levels were referred to their oncology nurse for referral to the appropriate professional. Patients in the EM group received written materials regarding cancer-related psychosocial issues and available resources. RESULTS: At 6 months, patients in the TM + EM group reported significantly less anxiety (HADS; P < .0001), depression (HADS; P = .0004), and overall distress (HADS; P < .0001) compared with patients in the EM group. CONCLUSIONS: Monthly monitoring of older patients' distress with TM and EM along with referral for appropriate help was found to be an efficient means of reducing patients' anxiety and depression compared with patients who received only EM.

Adaptation, Psychological↗

PubMed2006

A phase II study of gemcitabine and capecitabine in metastatic renal cancer: a report of Cancer and Leukemia Group B protocol 90008.

BACKGROUND: The objective of this study was to verify previous reports of activity with gemcitabine plus a fluoropyrimidine in patients with metastatic renal cell cancer in a multiinstitutional setting. METHODS: Eligibility included a Zubrod performance status from 0 to 2, no prior gemcitabine or fluoropyrimidine therapy, and normal organ function. Patients received gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 and capecitabine at a dose of 830 mg/m2 twice daily on Days 1 through 21 on a 28-day cycle with specified dose reductions for baseline renal insufficiency. The primary endpoint was the response rate, which was assessed every 8 weeks. The statistical plan tested the hypothesis that the response rate was 5% versus an alternative of 15%. RESULTS: Sixty patients were enrolled, and 4 of those patients never started treatment. Of the 56 evaluable patients, 79% of patients underwent prior nephrectomy, 75% of patients received prior systemic therapy, and 75% of patients had clear cell histology. Risk stratification revealed that 34%, 43%, and 16% of patients were in Risk Groups 1, 2, and 3, respectively. Toxicity (graded according to the National Cancer Institute's Common Toxicity Criteria [version 2.0]) included Grade 3 or 4 neutropenia in 45% of patients, Grade 2 or greater fatigue in 32% of patients, Grade 2 or greater nausea in 29% of patients, Grade 2 or greater hand-foot reaction in 39% of patients, and Grade 2 or greater diarrhea in 22% of patients. Six patients responded (11%; 95% confidence interval, 4-22%), and the overall median survival was 14.5 months. CONCLUSIONS: Gemcitabine plus capecitabine had modest activity in patients with metastatic renal cancer, although the degree of activity and its associated toxicity would not support further evaluation in a Phase III trial of unselected patients. More focused investigations to identify patients most likely to benefit or to enhance activity with additional agents would be reasonable.

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PubMed2006

Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162).

PURPOSE: To establish whether absolute prostate-specific antigen (PSA) value after androgen deprivation (AD) is prognostic in metastatic (D2) prostate cancer (PCa). PATIENTS AND METHODS: D2 PCa patients with baseline PSA of at least 5 ng/mL received 7 months induction AD. Patients achieving PSA of 4.0 ng/mL or less on months 6 and 7 are randomly assigned to continuous versus intermittent AD on month 8. Eligibility for this analysis required a prestudy PSA with at least two subsequent PSAs and that patients be registered at least 1 year before analysis date. Survival was defined as time to death after 7 months of AD. Associations were evaluated by proportional hazards regression models. RESULTS: One thousand one hundred thirty four of 1,345 eligible patients achieved a PSA of 4 ng/mL or less. At end of induction, 965 patients maintained PSA of 4 or less and 604 had a PSA of 0.2 ng/mL or less. After controlling for prognostic factors, patients with a PSA of 4 or less to more than 0.2 ng/mL had less than one third the risk of death (ROD) as those with a PSA of more than 4 ng/mL (P < .001). Patients with PSA of 0.2 ng/mL or less had less than one fifth the ROD as patients with a PSA of more than 4 ng/mL (P < .001) and had significantly better survival than those with PSA of more than 0.2 to 4 ng/mL or less (P < .001). Median survival was 13 months for patients with a PSA of more than 4 ng/mL, 44 months for patients with PSA of more than 0.2 to 4 ng/mL or less, and 75 months for patients with PSA of 0.2 ng/mL or less. CONCLUSION: A PSA of 4 ng/mL or less after 7 months of AD is a strong predictor of survival. This data should be used to tailor future trial design for D2 prostate cancer.

Adult↗

PubMed2006

Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel-Lindau gene status.

OBJECTIVE: To describe the relationship among patient characteristics, Von Hippel-Lindau (VHL) gene status and clinical outcome in metastatic renal cell carcinoma (RCC) in patients receiving vascular endothelial growth factor (VEGF)-targeted therapy. PATIENTS AND METHODS: All patients with metastatic RCC who received therapy with interferon-alpha plus bevacizumab, SU11248 or AG013736 at the authors' institution were considered. Clinical features were collected and activation status of the VHL gene (VHL) was determined from baseline paraffin-embedded tumour samples. Tumour response, time to tumour progression (TTP) and overall survival were recorded. RESULTS: Forty-three patients were evaluable for determination of VHL status and clinical response. There was an objective response in 18 patients (43%; 95% confidence interval 28-59%). The median TTP for the entire cohort was 8.1 months. There was an improved clinical outcome in patients with the following clinical features: male gender, lack of hepatic metastases, no previous radiation therapy and higher baseline haemoglobin level. Twenty-six patients (60%) had evidence of VHL mutation or promoter methylation; such patients had an objective response rate of 48%, vs 35% in patients with no VHL mutation or methylation. Patients with VHL methylation or a mutation predicted to truncate or shift the VHL reading frame had a median TTP of 13.3 months, vs 7.4 months in patients with none of these features (P = 0.06). CONCLUSION: VEGF-targeted therapy is active in metastatic RCC and the response can be associated with certain clinical features. The TTP with VEGF-targeted therapy might be prolonged in patients with VHL methylation or mutations that truncate or shift the VHL reading frame. Further investigation of VHL pathway components is needed to understand the biology of the response to VEGF-targeted agents in metastatic RCC.

Adult↗

PubMed2006

Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy.

BACKGROUND: APC8015 (sipuleucel-T) is a cellular prostate cancer vaccine containing autologous antigen-presenting cells (APC) loaded with PA2024, a recombinant prostatic acid phosphatase/granulocyte-macrophage-colony-stimulating factor fusion protein, as the immunogen. Bevacizumab is a recombinant antibody against vascular endothelial growth factor, a proangiogenic protein with inhibitory effects on APC. A clinical trial was conducted to determine the prostate-specific antigen (PSA) and immunomodulatory effects of this combination immunotherapy. METHODS: Patients with androgen-dependent prostate cancer who had received prior definitive therapy with nonmetastatic, recurrent disease as manifested by a rising PSA of between 0.4 ng/mL and 6.0 ng/mL were enrolled. APC8015 was given intravenously(i.v.) on Weeks 0, 2, and 4. Bevacizumab was given at a dose of 10 mg/kg i.v. on Weeks 0, 2, 4, and every 2 weeks thereafter until toxicity or disease progression. PSA changes were recorded and the PSA doubling time (PSADT) was calculated. Immune response versus PA2024 was measured at baseline and after treatment by T-cell proliferation and interferon-gamma enzyme-linked immunospot (ELISPOT) assays. RESULTS: Twenty-two patients were treated. One patient achieved a > or =50% decrease in PSA. Nine patients exhibited some decrease in PSA from baseline, ranging from 6% to 72%, with the PSA of 3 patients decreasing at least 25%. The median pretreatment PSADT for the 20 evaluable patients was 6.9 months and the median posttreatment PSADT was 12.7 months (P = .01). All patients demonstrated induction of an immune response against PA2024. CONCLUSIONS: The combination of APC8015 and bevacizumab induces an immune response and modulates PSA in patients with biochemically recurrent prostate cancer.

Acid Phosphatase↗

PubMed2006

Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer.

PURPOSE: Sipuleucel-T (APC8015) is an investigational immunotherapy product designed to stimulate T-cell immunity against prostatic acid phosphatase. A phase III study was undertaken to evaluate the safety and efficacy of sipuleucel-T in a placebo-controlled study. PATIENTS AND METHODS: A total of 127 patients with asymptomatic metastatic hormone refractory prostate cancer (HRPC) were randomly assigned in a 2:1 ratio to receive three infusions of sipuleucel-T (n = 82) or placebo (n = 45) every 2 weeks. On disease progression, placebo patients could receive APC8015F, a product made with frozen leukapheresis cells. RESULTS: Of the 127 patients, 115 patients had progressive disease at the time of data analysis, and all patients were followed for survival for 36 months. The median for time to disease progression (TTP) for sipuleucel-T was 11.7 weeks compared with 10.0 weeks for placebo (P = .052, log-rank; hazard ratio [HR], 1.45; 95%CI, 0.99 to 2.11). Median survival was 25.9 months for sipuleucel-T and 21.4 months for placebo (P = .01, log-rank; HR, 1.70; 95%CI, 1.13 to 2.56). Treatment remained a strong independent predictor of overall survival after adjusting for prognostic factors using a Cox multivariable regression model (P = .002, Wald test; HR, 2.12; 95%CI, 1.31 to 3.44). The median ratio of T-cell stimulation at 8 weeks to pretreatment was eight-fold higher in sipuleucel-T-treated patients (16.9 v 1.99; P < .001). Sipuleucel-T therapy was well tolerated. CONCLUSION: While the improvement in the primary end point TTP did not achieve statistical significance, this study suggests that sipuleucel-T may provide a survival advantage to asymptomatic HRPC patients. Supportive studies are underway.

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PubMed2006

Activities and accomplishments of the cancer and leukemia group B genitourinary committee.

The Cancer and Leukemia Group B Genitourinary (GU) Committee has developed a multidisciplinary approach to treatment of GU cancer and has integrated correlative science research into the major research themes of the GU Committee. In localized prostate cancer, trials have evaluated novel approaches in radiation therapy. For patients with recurrence after local therapy, a trial evaluating local recurrence with salvage prostatectomy and a study of systemic therapy with "peripheral androgen blockade" were undertaken. Major contributions have been made in developing and testing therapeutics for advanced, androgen-independent prostate cancer (ketoconazole, suramin, estramustine/docetaxel, and docetaxel/bevacizumab), and in developing predictive markers and algorithms to assess prognosis in these patients. Contributions in kidney cancer have included the development of novel trial methodology, such as the randomized discontinuation trial design, and the testing of antiangiogenics. In addition to these areas, future work of the committee will include further development of therapy for earlier-stage prostate cancer patients and bladder cancer patients.

Antineoplastic Agents↗

PubMed2006

A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer.

CG7870 is a replication-selective oncolytic adenovirus genetically engineered to replicate preferentially in prostate tissue. In a previous phase I/II clinical trial of intraprostatic delivery of CG7870 for locally recurrent prostate cancer this virus was well tolerated. In this phase I study CG7870 was administered as a single intravenous infusion in a group-sequential dose escalation design (1 x 10(10) to 6 x 10(12) viral particles (vp)) to 23 patients with hormone-refractory metastatic prostate cancer. Flulike symptoms (fever, fatigue, rigors, nausea, and/or vomiting) were the most common adverse events. Three therapy-related grade 3 adverse events were reported, one of which (fatigue) was serious. At doses greater than 10(12) vp all five patients experienced asymptomatic grade 1 to 2 transaminitis and/or isolated d-dimer elevations starting on day 2 through 8; dose escalation was therefore halted at 6 x 10(12) vp. All tested patients had CG7870 genomes present in the peripheral blood for at least 90 minutes after infusion; patients in the highest dose group had persistence of genomes through 29 days. A "secondary" or "delayed" peak in plasma CG7870 genome copies (defined as a >10-fold increase in CG7870 genomes from nadir concentration) suggestive of active viral replication and shedding into the bloodstream was detected in 16/23 (70%) patients. CG7870 was detected in the saliva of 3 patients, whereas all urine samples tested negative. All patients developed antibodies to CG7870. Dose-related increases in interleukins 6 and 10 (IL-6, IL-10) blood levels were detected. The peak IL-6 concentration after CG7870 treatment was associated with a transient, asymptomatic decrease in blood pressure. No partial or complete prostate-specific antigen (PSA) responses were observed; however, 5 patients had a decrease in serum PSA of 25% to 49% following a single treatment, including 3 of 8 patients at the highest dose levels.

Adenoviridae↗

PubMed2006

Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16.

BACKGROUND: The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial. METHODS: Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%-90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided. RESULTS: Three-month PSA level declines of 20%-40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P < .001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy. CONCLUSIONS: Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.

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PubMed2006

Maximal COX-2 immunostaining and clinical response to celecoxib and interferon alpha therapy in metastatic renal cell carcinoma.

BACKGROUND: Cyclooxygenase-2 (COX-2) plays a major role in the development of cancer through numerous mechanisms. COX-2 is expressed in the majority of renal cell carcinoma (RCC) tumors and correlates with stage, grade, and microvessel density. Based on potential additive or synergistic antitumor effects, interferon-alpha (IFNalpha) and celecoxib, an oral COX-2 inhibitor, were given to metastatic RCC patients in a Phase II trial. METHODS: Patients with untreated, metastatic RCC received IFNalpha 3 million units (MU) daily and celecoxib 400 mg orally (p.o.) twice daily continuously until disease progression or unacceptable toxicity. Pretreatment, paraffin-embedded RCC tumor samples were immunohistochemically stained for COX-2 expression and plasma basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels were assayed to determine predictive or prognostic potential. RESULTS: There were three partial responses among 25 patients treated (objective response rate, 12%; 95% confidence interval [CI], 3-31%). The observed median time to disease progression (TTP) for the entire cohort was 3.3 months. A significant association between maximal COX-2 staining and clinical response was observed: all patients who experienced an objective response demonstrated 3+ COX-2 tumor immunostaining (trend test: P=0.03). Therapy was well tolerated without cardiac or other notable toxicity. CONCLUSIONS: The addition of celecoxib to IFNalpha did not increase the objective response rate or TTP of this unselected cohort. Maximal COX-2 tumor immunostaining may identify RCC patents more likely to achieve clinical benefit with COX-2 inhibition in combination with IFNalpha. Further investigation of this combination in 3+ COX-2-overexpressing RCC tumors is warranted.

Administration, Oral↗

PubMed2006

A retrospective evaluation of second-line chemotherapy response in hormone-refractory prostate carcinoma: second line taxane-based therapy after first-line epothilone-B analog ixabepilone (BMS-247550) therapy.

BACKGROUND: Epothilones and taxanes interfere with microtubule function. Ixabepilone, which is an epothilone-B analog, has activity against taxane-resistant cell lines and as first-line therapy for men with hormone-refractory prostate carcinoma (HRPC). Clinical cross-resistance of ixabepilone and taxanes in HRPC is unknown. METHODS: Records were evaluated retrospectively from patients with HRPC who were treated on a randomized Phase II trial of ixabepilone with or without estramustine and who subsequently received taxane chemotherapy. Posttherapy declines in prostate-specific antigen (PSA) levels and time to PSA progression were defined by consensus criteria. The median survival was evaluated by using the Kaplan-Meier method. RESULTS: Forty-nine patients who received ixabepilone with estramustine (28 patients) or without estramustine (21 patients) subsequently received second-line taxane therapy. Second-line PSA declines > or = 50% were achieved by 51% of patients (95% confidence interval [95% CI], 33-66%). Second-line PSA declines > or = 50% were achieved by 61% of patients (95% CI, 42-78%) who achieved a first-line PSA decline > or = 50% with ixabepilone, compared with 33% of patients (95% CI, 13-59%) who did not (P = 0.08). Patients who discontinued first-line ixabepilone treatment for disease progression were less likely to achieve a PSA decline > or = 50% in response to second-line, taxane-based therapy compared with patients who discontinued for toxicity or patient preference (36% vs. 71%; P = 0.01). CONCLUSIONS: Second-line taxane chemotherapy after ixabepilone resulted in a substantial frequency of PSA declines. Although patients with ixabepilone-refractory disease were less likely to respond to second-line taxane chemotherapy, 36% did achieve a PSA response. These findings were consistent with incomplete clinical cross-resistance between the taxanes and the epothilones.

Aged↗

PubMed2006

Immunotherapy for prostate cancer.

Whereas androgen deprivation and chemotherapy have become the cornerstone of therapy for advanced prostate cancer, novel therapies are being developed that may expand upon currently available treatments. The identification of antigens expressed by prostate tissue and/or prostate cancer that are recognized by T cells or antibodies creates opportunities to develop novel immunotherapeutic approaches including tumor vaccines. Proteins expressed in prostate cancer including prostate-specific antigen, prostatic acid phosphatase, and prostate membrane antigen have been used as immunologic targets for immunotherapy. Moreover, innovations in cancer genomics and proteomics also will aid in the identification of immunologic targets. Emerging trials have demonstrated that immunotherapy may not only generate immune responses in patients, but also clinical responses. Future studies will be directed at capitalizing on these findings.

Antibodies, Neoplasm↗

PubMed2006

Adoptive immunotherapy by allogeneic stem cell transplantation for metastatic renal cell carcinoma: a CALGB intergroup phase II study.

A graft-versus-tumor effect through nonmyeloablative allogeneic stem cell transplantation (N-SCT) in metastatic renal cell carcinoma (RCC) has been reported. An Intergroup phase II trial was undertaken to define further the feasibility, toxicity and efficacy of this approach in a multi-institutional setting, Patients with cytokine-refractory, metastatic RCC were treated with N-SCT. The conditioning regimen was fludarabine 30 mg . m(-2) . d(-1) on day (d) -7 through d -3 and cyclophosphamide 60 mg . kg(-1) . d(-1) on d -4 and d -3. Patients received 2-8 x 10(6) CD34+ cells/kg of granulocyte colony-stimulating factor mobilized stem cells from a 6/6 HLA-matched sibling donor. Immunosuppression after transplantation included tacrolimus and methotrexate. Twenty-two patients were enrolled at 14 institutions. Greater than 90% donor T-cell chimerism was observed in 17 of 19 evaluable patients (89%) by d +120. No objective response was observed. Acute graft-versus-host disease (GVHD) was observed in 11 patients (50%). Chronic GVHD was reported in 5 patients (23%). There was 1 patient death from liver failure secondary to chronic GVHD. Regimen-related mortality was 2 of 22 (9%; liver failure, sepsis). Median survival time was 5.5 months (95% confidence interval, 3.9-12.0 months) and the median time to progression was 3.0 months (95% confidence interval, 2.3-4.2 months). N-SCT for metastatic RCC is feasible in a multi-institutional setting. Adequate donor T-cell engraftment was achieved in most patients before disease progression. A graft-versus-tumor effect was not observed in this study despite acute and chronic GVHD, thus highlighting the need for further understanding of this approach. Allogeneic SCT remains investigational in RCC.

Adult↗

PubMed2006

The case for secondary hormonal therapies in the chemotherapy age.

PURPOSE: Virtually all patients with high risk localized and metastatic prostate cancer who are treated with androgen deprivation therapy eventually have progressive clinical or biochemical disease despite this therapy. Despite this fact numerous therapies are available that target the interaction of androgen and androgen receptor in the castrate testosterone milieu and many clinical investigations are under way in this area. MATERIALS AND METHODS: This literature review focuses on the current clinical literature in support of secondary hormonal therapy. RESULTS: Despite low androgen levels the androgen receptor remains active through the amplification, mutation or alteration of coactivator function. These observations suggest that secondary hormonal therapies remain a reasonable clinical approach. Such approaches can be receptor or ligand directed. Receptor directed approaches to secondary hormonal therapy are antiandrogen withdrawal, sequential use of antiandrogens and estrogenic compounds. Ligand directed therapies are adrenal cortex inhibitors, such as ketoconazole and others in clinical development. Furthermore, in the context of androgen independent tumor growth in patients with metastatic disease clinicians are now faced with the choice of using chemotherapy or secondary hormonal manipulations. Appropriate patient selection is a critical component to the effective use of these agents. CONCLUSIONS: The modest activity of these secondary therapies challenges the notion that advancing prostate cancer uniformly becomes hormone refractory. It offers an alternative to the early use of chemotherapy in patients with androgen independent disease.

Androgen Antagonists↗

PubMed2006

High risk biochemical relapse and the timing of androgen deprivation therapy.

PURPOSE: Although the timing of androgen deprivation therapy in patients with prostate specific antigen-only relapse remains controversial, a large amount of data exists supporting the use of androgen deprivation early in the clinical course in patients with high risk localized prostate cancer as well as in those with metastatic disease. We offer guidance on its use in patients with prostate specific antigen recurrence only. MATERIALS AND METHODS: We reviewed recent data on androgen deprivation for nonmetastatic prostate cancer, including updates from phase III, randomized studies of androgen deprivation in conjunction with radiation therapy or surgery in patients with high risk features. RESULTS: We commented on the extent to which these data on androgen deprivation for nonmetastatic prostate cancer could be extrapolated to the setting of recurrent disease. In addition, we reviewed retrospective analyses of androgen deprivation in patients with prostate specific antigen-only relapse and prognostic data regarding prostate specific antigen doubling time in recurrent disease. Furthermore, consideration was given to rapid prostate specific antigen doubling time as an indication for androgen deprivation. CONCLUSIONS: In patients with nonmetastatic prostate cancer with high risk features as well as in those with serological (prostate specific antigen-only) relapse androgen deprivation before the development of metastatic disease is indirectly supported by long-term outcomes in a series of clinical trials and retrospective data sets. Furthermore, prognostic data suggest that early androgen deprivation may be most beneficial in patients with serological relapse with prostate specific antigen doubling times less than 12 months.

Androgen Antagonists↗

PubMed2006

Clinical and immunological characteristics of patients with serologic progression of prostate cancer achieving long-term disease control with granulocyte-macrophage colony-stimulating factor.

PURPOSE: We describe the clinical and immunological characteristics of patients with biochemically relapsed prostate cancer who achieved long-term disease control with GM-CSF (Leukine). MATERIALS AND METHODS: A total of 30 patients with prostate cancer and nonmetastatic recurrent disease, as manifested by increasing PSA between 0.4 and 6.0 ng/ml after prior definitive therapy, were enrolled in a phase II trial. Patients received 250 microg/m2 GM-CSF daily subcutaneously on days 1 through 14 of a 28-day cycle until PSA or objective progression. The patient and disease characteristics of patients who remained without evidence of disease progression beyond 4 years were examined. Additionally, flow cytometry was performed in peripheral blood to characterize monocyte and dendritic cells. RESULTS: Seven of 29 evaluable patients (24%) remained free of disease progression at a median of 5.1 years (range 4.5 to 5.6 or greater) from the start of GM-CSF therapy. Patients on long-term GM-CSF tended to have lower initial T stage, Gleason score and pretreatment PSA. An increase in the number of circulating monocytes and dendritic cells was observed after 14 days of GM-CSF treatment. These values returned to baseline during the 14-day off period. CONCLUSIONS: GM-CSF modulates PSA in androgen dependent, biochemically relapsed cases. A substantial proportion of patients achieve long-term disease control. The clinical characteristics described may help select patients for future clinical trials with GM-CSF or other immunomodulators. Additional investigation is required to define the immunological mechanism of GM-CSF in prostate cancer.

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