Validation of a new prognostic model to easily predict outcome in renal cell carcinoma: the GRANT score applied to the ASSURE trial population.

Background: Prognostic scores have been developed to estimate the risk of recurrence and the probability of survival after nephrectomy for renal cell carcinoma (RCC). The use of these tools, despite being helpful to plan a customized schedule of follow-up, to the patient's tailored counselling and to select individuals who could potentially benefit from adjuvant treatment, currently is not routine, due to their relative complexity and to the lack of histological data (i.e. necrosis). Patients and methods: We developed a simple score called GRade, Age, Nodes and Tumor (GRANT) based on four easily obtained parameters: Fuhrman grade, age, pathological nodal status and pathological tumor size. Patients with 0 or 1 factor are classified as favorable risk, whereas patients with two or more risk factors as unfavorable risk. The large population of RCC patients from the ASSURE adjuvant trial was used as independent dataset for this external validation, to investigate the prognostic value of the new score in terms of disease-free survival and overall survival and to evaluate its possible application as predictive tool. Statistical analyses were carried out by the Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute (Boston, USA) for the ASSURE trial patients' population. Results: The performance of the new model is similar to that of the already validated score systems, but its strength, compared with the others already available, is the ease and clarity of its calculation, with great speed of use during the clinical practice. Limitations are the use of the Fuhrman nuclear grade, not valid for rare histologies, and the TNM classification modifications over time. Conclusion: The GRANT score demonstrated its potential usefulness for clinical practice. ClinicalTrials.gov Identifier for the ASSURE trial: NCT00326898.

Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC-A Possible Path Forward.

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Employment outcomes among survivors of common cancers: the Symptom Outcomes and Practice Patterns (SOAPP) study.

INTRODUCTION: Risk factors for employment difficulties after cancer diagnosis are incompletely understood, and interventions to improve post-cancer employment remain few. New targets for intervention are needed. METHODS: We assessed a cohort of 530 nonmetastatic cancer patients (aged ≤ 65 years, >6 months from diagnosis, off chemo- or radiotherapy) from the observational multi-site Symptom Outcomes and Practice Patterns study. Participants reported employment change, current employment, and symptoms. Groups were based on employment at survey (working full- or part-time versus not working) and whether there had been a change due to illness (yes versus no). The predictive power of symptom interference with work was evaluated for employment group (working stably versus no longer working). Race/ethnicity, gender, cancer type, therapy, and time since diagnosis were also assessed. Association between employment group and specific symptoms was examined. RESULTS: The cohort was largely non-Hispanic white (76 %), female (85 %), and diagnosed with breast cancer (75 %); 24 % reported a change in employment. On multivariable analysis, participants with at least moderate symptom interference were more likely to report no longer working than their less effected counterparts (odds ratio (OR) = 8.0, 95 % CI, 4.2-15.4), as were minority participants compared with their non-Hispanic white counterparts (OR = 3.2, 95 % CI, 1.8-5.6). Results from the multiple regression model indicated the combination of fatigue (OR = 2.3, 95 % CI, 1.1-4.7), distress (OR = 3.9, 95 % CI, 1.7-9.0), and dry mouth (OR = 2.6, 95 % CI, 1.1-6.2) together with race/ethnicity and time since diagnosis adequately accounted for employment group. CONCLUSIONS: Our findings support the hypothesis that residual symptom burden is related to post-cancer employment: Residual symptoms may be targets for intervention to improve work outcomes among cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: This analysis examines whether increased symptom burden is associated with a change to not working following a cancer diagnosis. We also examined individual symptoms to assess which symptoms were most strongly associated with not working after a cancer diagnosis. Our hope is that we will be able to use this information to both screen survivors post-active treatment as well as target high-risk symptoms for further and more aggressive intervention, in an attempt to improve post-cancer work outcomes.

A randomized phase II study of ixabepilone (BMS-247550) given daily x 5 days every 3 weeks or weekly in patients with metastatic or recurrent squamous cell cancer of the head and neck: an Eastern Cooperative Oncology Group study.

Ixabepilone is a tubulin-polymerizing agent with potential activity in squamous cell carcinoma of the head and neck (SCCHN). Patients were eligible who had incurable, measurable SCCHN and less than two prior regimens for metastatic/recurrent disease. Eastern Cooperative Oncology Group performance status of less than or equal to one and adequate renal/hepatic/hematological function were required. Patients were randomly assigned to receive ixabepilone 6 mg/m(2)/day x 5 days every 21 days (arm A) or 20 mg/m(2) on days 1, 8, and 15 of a 28-day cycle (arm B). Each arm accrued taxane-naive and -exposed strata in a two-stage design. The primary end point was response. Eighty-five eligible patients entered; there was one response in a taxane-exposed patient among 32 patients on arm A. Five of 35 taxane-naive patients on arm B had partial responses (14%). No taxane-exposed patient on arm B responded. Common grades 3 and 4 toxic effects were fatigue, neutropenia, and sensory/motor neuropathy. Median survival for arm A taxane-naive and taxane-exposed patients is 5.6 and 6.5 months; for arm B, taxane-naive and taxane-exposed patients is 7.8 and 6.5 months. Weekly ixabepilone 20 mg/m(2) is active in taxane-naive patients with SCCHN. A high incidence of motor and sensory grade 3 neuropathy resulted at this dose and schedule. Further development of ixabepilone in previously treated head and neck cancer is not warranted on the basis of these data.

Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study.

PURPOSE: To evaluate the response rate, toxicity profile, and pharmacokinetics of ecteinascidin-743 (ET-743) as first-line therapy in patients with unresectable advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: Thirty-six patients with STS were enrolled onto the study between September 1999 and August 2000. Patients were treated with 1.5 mg/m2 of ET-743 given as a 24-hour continuous intravenous (IV) infusion every 21 days. Pharmacokinetic sampling was performed in 23 patients. RESULTS: One complete and five partial responses were achieved in 35 assessable patients for an overall response rate of 17.1% (95% CI, 6.6% to 33.6%). In addition, one patient had a minor response, leading to an overall clinical benefit of 20%. Neutropenia and transaminitis were the main grade 3 to 4 toxicities, which occurred in 33% and 36% of the patients. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11% to 41%) and 72% (95% CI, 59% to 88%), respectively. Total body clearance (L/h) was not significantly correlated with body-surface area (r = -0.28; P = .21). Mild hepatic impairment or the extent of prior cytotoxic therapy does not seem to contribute significantly to the high interpatient variability (49%) in the clearance of this drug. Severity of treatment-related toxicity was not correlated with pharmacokinetic variables. CONCLUSION: ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.

Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate.

BACKGROUND: Medical or surgical castration is effective in advanced prostate cancer but with profound side-effects, particularly on sexual function. Effective, less toxic therapies are needed. This study examined whether the addition of finasteride to high-dose bicalutamide enhanced disease control, as measured by additional decreases in serum prostate-specific antigen (PSA). PATIENTS AND METHODS: Forty-one patients with advanced prostate cancer received bicalutamide (150 mg/day). Finasteride (5 mg/day) was added at first PSA nadir. Serum PSA was measured every 2 weeks until disease progression. Questionnaires were administered to assess sexual function. RESULTS: Median follow-up is 3.9 years. At the first PSA nadir, median decrease in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second PSA nadir and median decrease of 98.5% from baseline. Median time to each nadir was 3.7 and 5.8 weeks, respectively. Median time to treatment failure was 21.3 months. Toxicities were minor, including gynecomastia. Seventeen of 29 (59%) and 12 of 24 (50%) men had normal sex drive at baseline and at second PSA nadir, respectively. One-third of men had spontaneous erection at both time points. CONCLUSION: Finasteride provides additional intracellular androgen blockade when added to bicalutamide. Duration of control is comparable to castration, with preserved sexual function in some patients.

Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy.

PURPOSE: To assess the efficacy of the marine-derived alkaloid ecteinascidin 743 (ET-743) in patients with soft tissue sarcomas that progressed despite prior conventional chemotherapy and to characterize the pharmacokinetic profiles of ET-743 in this patient population. PATIENTS AND METHODS: Thirty-six previously treated soft tissue sarcoma patients from three institutions received ET-743 as a 24-hour continuous intravenous (IV) infusion at a dose of 1,500 microg/m(2) every 3 weeks. Pharmacokinetic studies were also performed. Patients were restaged every two cycles for response by objective criteria. RESULTS: Objective responses were observed in three patients, with one complete response and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Two minor responses (43% and 47% tumor reduction) were observed, for an overall clinical benefit rate of 14%. The predominant toxicities were neutropenia and self-limited transaminitis of grade 3 to 4 severity in 34% and 26% of patients, respectively. The estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. The maximum observed plasma concentration and total plasma clearance of ET-743 (mean +/- standard deviation), 1.04 +/- 0.48 ng/mL and 35.6 +/- 16.2 L/h/m(2), respectively, were consistent with previously reported values from phase I studies of the drug given as a 24-hour IV infusion. CONCLUSION: ET-743 is a promising new option for the management of several histologic subtypes of sarcoma. Durable objective responses were obtained in a subset of sarcoma patients with disease progression despite prior chemotherapy. Additionally, the relatively high survival rate noted in this series of previously treated patients further justifies development of this agent.

A practical method to achieve prostate gland immobilization and target verification for daily treatment.

PURPOSE: A practical method to achieve prostate immobilization and daily target localization for external beam radiation treatment is described. METHODS AND MATERIALS: Ten patients who underwent prostate brachytherapy using permanent radioactive source placement were selected for study. To quantify prostate motion both with and without the presence of a specially designed inflatable intrarectal balloon, the computerized tomography-based coordinates of all intraprostatic radioactive sources were compared over 3 consecutive measurements at 1-min intervals. RESULTS: The placement and inflation of the intrarectal balloon were well tolerated by all patients. The mean (range) displacement of the prostate gland when the intrarectal balloon was present vs. absent was 1.3 (0-2.2) mm vs. 1.8 (0-9.1) mm (p = 0.03) at 2 min respectively. The maximum displacement in any direction (anterior-posterior, superior-inferior, or right-left) when the intrarectal balloon was inflated vs. absent was reduced to < or =1 mm from 4 mm. CONCLUSIONS: Both prostate gland immobilization and target verification are possible using a specially designed inflatable intrarectal balloon. Using this device, the posterior margin necessary on the lateral fields to ensure dosimetric coverage of the entire prostate gland could be safely reduced to 5 mm and treatment could be set up and verified using a lateral portal image.

Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer.

PURPOSE: We sought to evaluate the effects of chemotherapy-induced ovarian failure on bone loss and markers of skeletal turnover in a prospective longitudinal study of young women with breast cancer receiving adjuvant chemotherapy. PATIENTS AND METHODS: Forty-nine premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated within 4 weeks of starting chemotherapy (baseline), and 6 and 12 months after starting chemotherapy with dual-energy absorptiometry and markers of skeletal turnover osteocalcin and bone-specific alkaline phosphatase. Chemotherapy-induced ovarian failure was defined as a negative pregnancy test, greater than 3 months of amenorrhea, and a follicle-stimulating hormone > or = 30 MIU/mL at the 12-month evaluation. RESULTS: Among the 35 women who were defined as having ovarian failure, highly significant bone loss was observed in the lumbar spine by 6 months and increased further at 12 months. The median percentage decrease of bone mineral density in the spine from 0 to 6 months and 6 to 12 months was -4.0 (range, -10.4 to +1.0; P =.0001) and -3.7 (range, -10.1 to 9.2; P =.0001), respectively. In contrast, there were no significant decreases in bone mineral density in the 14 patients who retained ovarian function. Serum osteocalcin and bone specific alkaline phosphatase, markers of skeletal turnover, increased significantly in the women who developed ovarian failure. CONCLUSION: Chemotherapy-induced ovarian failure causes rapid and highly significant bone loss in the spine. This may have implications for long-term breast cancer survivors who may be at higher risk for osteopenia, and subsequently osteoporosis. Women with breast cancer who develop chemotherapy-induced ovarian failure should have their bone density monitored and treatments to attenuate bone loss should be evaluated.

Membrane-fusing capacity of the human immunodeficiency virus envelope proteins determines the efficiency of CD+ T-cell depletion in macaques infected by a simian-human immunodeficiency virus.

The mechanism of the progressive loss of CD4+ T lymphocytes, which underlies the development of AIDS in human immunodeficiency virus (HIV-1)-infected individuals, is unknown. Animal models, such as the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae, can assist studies of HIV-1 pathogenesis. Serial in vivo passage of the nonpathogenic SHIV-89.6 generated a virus, SHIV-89.6P, that causes rapid depletion of CD4+ T lymphocytes and AIDS-like illness in monkeys. SHIV-KB9, a molecularly cloned virus derived from SHIV-89.6P, also caused CD4+ T-cell decline and AIDS in inoculated monkeys. It has been demonstrated that changes in the envelope glycoproteins of SHIV-89.6 and SHIV-KB9 determine the degree of CD4+ T-cell loss that accompanies a given level of virus replication in the host animals (G. B. Karlsson et. al., J. Exp. Med. 188:1159-1171, 1998). The envelope glycoproteins of the pathogenic SHIV mediated membrane fusion more efficiently than those of the parental, nonpathogenic virus. Here we show that the minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity is sufficient to convert SHIV-89.6 into a virus that causes profound CD4+ T-lymphocyte depletion in monkeys. We also studied two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins by different mechanisms. Each of these changes attenuated the CD4+ T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4+ T lymphocytes in vivo.

Fluorouracil modulation in colorectal cancer: lack of improvement with N -phosphonoacetyl- l -aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule--an Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study.

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.

Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

Phase II evaluation of menogaril in advanced prostate cancer: Eastern Cooperative Oncology Group EST P-A885.

Menogaril is a semisynthetic anthracycline that is less cardiotoxic than doxorubicin in a preclinical model. We conducted a phase II trial to determine the activity of menogaril in hormone-refractory prostate cancer. Between October 1985 and November 1987, 32 eligible patients were enrolled and were divided into good- and poor-risk categories, the latter being defined by prior radiotherapy to less than one third of the marrow-containing skeleton. Good-risk patients received a starting dose of 200 mg/m2 by 60-minute IV infusion, whereas the poor-risk patients received 160 mg/m2. Treatment was repeated every 3 weeks until disease progression. Menogaril caused leukopenia in 90% of patients, of whom 47% had grade III or IV toxicity. Thrombocytopenia was uncommon and mild, with only three patients (9%) experiencing grade II toxicity. Nonhematologic toxicity included mucositis (9%), and mild weight loss in 33% of patients. Nine patients (28%) had stable disease of 3 or more months' duration. There were no objective partial or complete responses. The median time to progression for the entire group was 10 weeks, and the median survival time for all patients was 24 weeks. Because of appreciable toxicity and limited antitumor activity, further study of menogaril cannot be recommended in hormone-refractory prostate cancer.

Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer.

OBJECTIVES: To retrospectively evaluate the response to treatment with PC-SPES, an herbal supplement, because patients with androgen-independent prostate cancer have limited treatment options. METHODS: A retrospective analysis was performed of patients with prostate cancer progression despite androgen ablation therapy who were treated with PC-SPES (3 capsules twice daily). We explored potential predictors of response. RESULTS: Twenty-three patients with androgen-independent prostate cancer were treated. The median age was 70 years. Eighteen patients had received prior secondary hormonal treatment and 10 prior chemotherapy. With a median follow-up of 8 months, 20 (87%; 95% confidence interval 66% to 97%) of 23 patients experienced a post-therapy decline in prostate-specific antigen (PSA). The median decline in PSA among these patients was 40% (range 1% to 88%). Of 23 patients, 12 (52%; 95% confidence interval 31% to 73%) had a greater than 50% decline in PSA. The median duration of the PSA response was 2.5 months (range 1 to 9+); the median time from the start of therapy to PSA progression was 6 months (range 2 to 12). Seven patients died of progressive prostate cancer. Toxicity was mild and included nipple tenderness, nausea, and diarrhea. One patient with a known history of coronary artery disease developed angina. In univariate analyses, older patients and those with a longer duration of initial androgen ablation therapy were more likely to respond to PC-SPES. CONCLUSIONS: PC-SPES is a well-tolerated and active treatment for androgen-independent prostate cancer. Additional testing is necessary to identify the active components of PC-SPES and its role in the treatment of patients with androgen-independent prostate cancer.

Her-2-neu expression and progression toward androgen independence in human prostate cancer.

BACKGROUND: Human prostate cancers are initially androgen dependent but ultimately become androgen independent. Overexpression of the Her-2-neu receptor tyrosine kinase has been associated with the progression to androgen independence in prostate cancer cells. We examined the expression of Her-2-neu in normal and cancerous prostate tissues to assess its role in the progression to androgen independence. METHODS: Prostate cancer tissue sections were obtained from 67 patients treated by surgery alone (UNT tumors), 34 patients treated with total androgen ablation therapy before surgery (TAA tumors), and 18 patients in whom total androgen ablation therapy failed and who developed bone metastases (androgen-independent [AI] disease). The sections were immunostained for Her-2-neu, androgen receptor (AR), prostate-specific antigen (PSA), and Ki-67 (a marker of cell proliferation) protein expression. Messenger RNA (mRNA) levels and gene amplification of Her-2-neu were examined by RNA in situ hybridization and fluorescent in situ hybridization(FISH), respectively, in a subset of 27 tumors (nine UNT, 11 TAA, and seven AI). All statistical tests were two-sided. RESULTS: Her-2-neu protein expression was statistically significantly higher in TAA tumors than in UNT tumors with the use of two different scoring methods (P =.008 and P =.002). The proportion of Her-2-neu-positive tumors increased from the UNT group (17 of 67) to the TAA group (20 of 34) to the AI group (14 of 18) (P<.001). When compared with UNT tumors, tumor cell proliferation was higher in AI tumors (P =.014) and lower in TAA tumors (P<.001). All tumors expressed AR and PSA proteins. Although Her-2-neu mRNA expression was high in TAA and AI tumors, no Her-2-neu gene amplification was detected by FISH in any of the tumor types. CONCLUSIONS: Her-2-neu expression appears to increase with progression to androgen independence. Thus, therapeutic targeting of this tyrosine kinase in prostate cancer may be warranted.

Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials.

PURPOSE: To identify factors that are prognostic for survival in patients with metastatic melanoma treated in eight Eastern Cooperative Oncology Group (ECOG) trials conducted over the past 25 years. METHODS: We identified common, significant patient characteristics collected at baseline on 1,362 eligible patients for inclusion in a pooled analysis. Proportional hazards models were used to examine simultaneously the effects of multiple covariates on survival. RESULTS: Median survival was 6.4 months (95% confidence interval, 6.1 to 6.9 months.) Factors conferring the greatest increased risk of death included number of metastatic sites (relative risk [RR] = 1.12), ECOG performance status of 1 or more (RR = 1.49), or metastatic disease in the gastrointestinal (GI) tract (RR = 1.49), liver (RR = 1.44), pleura (RR = 1.35), or lung (RR = 1.19). Prior immunotherapy (RR = 0.84) and female sex (RR = 0. 87) were associated with prolonged survival. Although only 12% of patients responded to protocol treatment, landmark analysis showed this to be a significant prognostic factor (RR = 0.57). A model based on three recent studies in which baseline values for alkaline phosphatase, lactate dehydrogenase (LDH), and platelets were available identified an increased number of sites of metastasis (RR = 1.30), abnormal LDH (RR = 1.89), abnormal alkaline phosphatase (RR = 1.76), abnormal platelets (RR = 1.63), and GI metastases (RR = 1. 66) as prognostic for poorer survival. Response to treatment, when examined by landmark analysis of studies with laboratory parameters, was associated with decreased risk of death (RR = 0.47). CONCLUSION: This study demonstrates the importance and utility of laboratory parameters as prognostic factors for survival and confirmed the deleterious effects of multiple metastatic sites. Prior immunotherapy and female sex were associated with improved prognosis. Prognostic factors identified in this analysis are consistent with the findings of prior published studies and argue for the adoption of laboratory findings in the staging systems that are used for entry and stratification of clinical trials in the future.

Vinorelbine and estramustine in androgen-independent metastatic prostate cancer: a phase II study.

BACKGROUND: The aim of this study was to determine the safety and activity of vinorelbine in combination with estramustine in men with androgen-independent metastatic prostate cancer. METHODS: Twenty-five men with androgen-independent metastatic prostate cancer were treated with the combination of vinorelbine and estramustine. Vinorelbine 25 mg/m(2) was administered by intravenous bolus on Days 1 and 8. Estramustine 140 mg was administered three times a day by mouth on Days 1 through 14. Treatment was repeated every 21 days. RESULTS: A total of 132 cycles of treatment were administered. The median number of cycles per patient was 5 (range: 1-16). Mild Grade 1 or 2 gastrointestinal toxicity and fatigue were the most common adverse effects. Hematologic toxicity was minimal. Treatment resulted in a sustained > 50% decrease in serum prostate-specific antigen (PSA) in 6 of 25 patients (24% of patients; 95% confidence interval (CI) 9-45%). The median duration of PSA response was 10 weeks (range: 3-39 weeks). Of the five men with bidimensionally measurable disease, none achieved a complete or partial response. There were no documented improvements in post-treatment bone scans. Median overall survival time was 14.1 months. CONCLUSIONS: The combination of vinorelbine and estramustine is a well-tolerated and modestly active regimen in men with androgen-independent metastatic prostate cancer.

Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy.

PURPOSE: Larger prostate gland volumes have been associated with long-term urinary morbidity in prostate interstitial radiation therapy utilizing ultrasound image guidance technique. This study was performed to identify the clinical and technical predictors of acute urinary retention following magnetic-resonance (MR)-guided prostate interstitial brachytherapy. METHODS AND MATERIALS: Fifty patients underwent MR-guided prostate brachytherapy between December 1997 and March 1999. Patient selection was limited to men with stage T1cNXM0 disease, PSA of less than10 ng/mL, biopsy Gleason score not more than 3 + 4, and endorectal coil MR stage T2 disease. Dosimetry plans were developed in the operating room and (125)Iodine sources were implanted using MR real-time guidance. The peripheral zone (PZ) of the prostate gland was defined as the clinical target volume (CTV) and the minimum prescribed dose to the CTV was 137 Gy. The volumes of the PZ, transition zone (TZ), and total prostate gland volume were also determined by MR. Individual source strength ranged from 0.35 to 0.54 microGym(2)/h (NIST 99, median 0.46 microGym(2)/h) and the total implanted activity ranged from 17.0 to 43.1 mCi (median, 28.1 mCi) using 43-120 seeds (median, 79). The seeds were placed using MR-compatible biopsy needles (14-28, median, 19). RESULTS: The ability of clinical (MR defined prostate, PZ, and TZ volumes) and technical (number of catheters, number of seeds implanted, and total activity) factors to predict AUR for 50 men undergoing MR-guided prostate interstitial brachytherapy were evaluated using univariable and logistic regression multivariable analyses. Six men (12%) experienced AUR within 24 h after removal of the Foley catheter subsequent to prostate brachytherapy. The total number of seeds (p = 0.05), MR determined prostate volume (p < 0.01), and the MR-determined TZ volume (p < 0.01) were significant predictors of AUR on univariable analysis. Utilizing a multivariable logistic regression analysis, the TZ volume was the only significant predictor of AUR (p < 0.01). The prostate volume is highly correlated to the TZ volume (Spearman correlation coefficient of 0. 91) and was thus significant in the univariable analysis; however, the prostate volume did not add prognostic value in multivariable analysis. CONCLUSION: Benign prostatic hyperplasia (BPH) resulting in an enlarged TZ volume, is the most important predictor of AUR following MR-guided prostate interstitial radiation therapy. Although AUR was significant (60%) in men with moderate BPH (TZ volume >/= 50 cc), it was also self-limiting.

Phase II study of cisplatin and paclitaxel in advanced carcinoma of the urothelium: an Eastern Cooperative Oncology Group Study.

PURPOSE: Cisplatin and paclitaxel are active agents in advanced urothelial cancer. A phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multi-institutional setting. PATIENTS AND METHODS: Fifty-two patients with advanced urothelial carcinoma were treated on one day with paclitaxel 175 mg/m(2) over 3 hours followed by cisplatin 75 mg/m(2), both intravenously, every 21 days. Cycles were repeated every 21 days until progression or a maximum of six cycles. RESULTS: Twenty-six patients obtained an objective response, for an overall response rate of 50% (95% confidence interval, 36% to 64%). Four patients achieved complete clinical responses. The median overall survival time for the group was 10.6 months. Toxicity was moderate, with granulocytopenia and neurotoxicity being the most common side effects noted. CONCLUSION: The combination of cisplatin and paclitaxel is active in advanced urothelial cancer. Responses in visceral, nodal, and soft tissues sites were observed. Granulocytopenia without fever and grade 2/3 neurotoxicity were common. The confidence interval of the overall response rate in this study overlaps most of the other reported regimens. The optimal therapy for advanced urothelial cancer remains undefined.