Cost-effectiveness of gene-expression profiling for tumor-site origin.

OBJECTIVES: Gene-expression profiling (GEP) reliably supplements traditional clinicopathological information on the tissue of origin (TOO) in metastatic or poorly differentiated cancer. A cost-effectiveness analysis of GEP TOO testing versus usual care was conducted from a US third-party payer perspective. METHODS: Data on recommendation changes for chemotherapy, surgery, radiation therapy, blood tests, imaging investigations, and hospice care were obtained from a retrospective, observational study of patients whose physicians received GEP TOO test results. The effects of chemotherapy recommendation changes on survival were based on the results of trials cited in National Comprehensive Cancer Network and UpToDate guidelines. Drug and administration costs were based on average doses reported in National Comprehensive Cancer Network guidelines. Other unit costs came from Centers for Medicare & Medicaid Services fee schedules. Quality-of-life weights were obtained from literature. Bootstrap analysis estimated sample variability; probabilistic sensitivity analysis addressed parameter uncertainty. RESULTS: Chemotherapy regimen recommendations consistent with guidelines for final tumor-site diagnoses increased significantly from 42% to 65% (net difference 23%; P<0.001). Projected overall survival increased from 15.9 to 19.5 months (mean difference 3.6 months; two-sided 95% confidence interval [CI] 3.2-3.9). The average increase in quality-adjusted life-months was 2.7 months (95% CI 1.5-4.3), and average third-party payer costs per patient increased by $10,360 (95% CI $2,982-$19,192). The cost per quality-adjusted life-year gained was $46,858 (95% CI $13,351-$104,269). CONCLUSIONS: GEP TOO testing significantly altered clinical practice patterns and is projected to increase overall survival, quality-adjusted life-years, and costs, resulting in an expected cost per quality-adjusted life-year of less than $50,000.

Unique patterns of metastases in common and rare types of malignancy.

This review on the unique patterns of metastases by common and rare types of cancer addresses regional lymphatic metastases but also demonstrates general principles by consideration of vital organ metastases. These general features of successfully treated metastases are relationships to basic biological behavior as illustrated by disease-free interval, organ-specific behavior, oligo-metastatic presentation, genetic control of the metastatic pattern, careful selection of patients for surgical resection, and the necessity of complete resection of the few patients eligible for long-term survival after resection of vital organ metastasis. Lymph node metastases, while illustrating these general features, are not related to overall survival because lymph node metastases themselves do not destroy a vital organ function, and therefore have no causal relationship to overall survival. When a cancer cell spreads to a regional lymph node, does it also simultaneously spread to the systemic site or sites? Alternatively, does the cancer spread to the regional lymph node first and then it subsequently spreads to the distant site(s) after an incubation period of growth in the lymph node? Of course, if the cancer is in its incubation stage in the lymph node, then removal of the lymph node in the majority of cases with cancer cells may be curative. The data from the sentinel lymph node era, particularly in melanoma and breast cancer, is consistent with the spectrum theory of cancer progression to the sentinel lymph node in the majority of cases prior to distant metastasis. Perhaps, different subsets of cancer may be better defined with relevant biomarkers so that mechanisms of metastasis can be more accurately defined on a molecular and genomic level.

C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial.

BACKGROUND: Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen-independent prostate cancer (AIPC) who are initiating docetaxel-based chemotherapy. METHODS: Baseline plasma samples were stored (-80 degrees C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo-controlled trial comparing weekly docetaxel plus high-dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate-specific antigen (PSA) decline. RESULTS: C-reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20-1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52-5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60-0.92 [P = .007]). CONCLUSIONS.: Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel-based therapy.

Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer.

BACKGROUND: DN-101 is a new, high-dose, oral formulation of calcitriol under investigation for the treatment of cancer. We sought to evaluate the tolerability and pharmacokinetics (PK) of weekly doses of DN-101 in patients with advanced cancer. METHODS: Patients who completed a previously reported single dose escalation study of DN-101 [Beer et al. (2005) Clin Cancer Res 11:7794-7799] were eligible for this continuation weekly dosing study. Cohorts of 3-10 patients were treated at doses of 15, 30, 45, 60, and 75 microg calcitriol. Once 45 microg was established as the maximum tolerated dose (MTD), this cohort was expanded to include 18 patients. Dose limiting toxicity (DLT) was defined as > or =grade 2 hypercalcemia or > or =grade 3 persistent treatment-related toxicities. RESULTS: Thirty-seven patients were recruited. DLT of transient reversible grade 2 hypercalcemia (serum calcium of 11.6-12.5 mg/dL) occurred in two of six patients treated with 60 microg of DN-101. No DLT was observed in the 18 patients who received DN-101 weekly at 45 microg. Overall, DN-101 was well tolerated. The most frequent adverse events were fatigue (27%), hypercalcemia (19%, including five grade 1, two grade 2, and no grade 3 or 4 events), and grade 1 nausea (16%). PK parameters following repeat dosing were comparable to those for the initial dose (n = 4). CONCLUSION: The MTD for weekly DN-101 was established as 45 mug. The DLTs observed were two episodes of rapidly reversible grade 2 hypercalcemia in two of the six patients treated at 60 microg weekly. Repeat doses of DN-101 at 45 microg weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients.

Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of calcitriol, in patients with cancer.

BACKGROUND: Intermittent administration allows substantial dose escalation of calcitriol but limited bioavailability of the commercially available formulations at high doses is limiting. In this dose escalation study, we sought to evaluate the tolerability and pharmacokinetics of a single oral dose of DN-101, a high-dose calcitriol formulation. METHODS: DN-101 doses were escalated in sequential groups of three to six patients with advanced solid tumors. Dose-limiting toxicity was defined as grade > or =2 hypercalcemia or grade > or =3 persistent treatment-related toxicities. Single-dose administration of 15, 30, 60, 75, 90, 105, 135, and 165 mug was tested. RESULTS: Thirty-eight patients were enrolled in 2002 and 2003. The median age was 70 years (range, 44-91 years). Dose escalation was stopped at the 165 microg level when the number of capsules required at one time reached 11. No dose-limiting toxicities occurred. Transient and self-limited grade 3 toxicities were hyponatremia (2) and proteinuria (1). A dose-proportional increase in peak concentration (C(max)) and area under the concentration curve (AUC) was seen across the full range of DN-101 doses tested. At the 165 microg dose, C(max) was 6.21 +/- 1.99 ng/mL, AUC(0-24) was 41.3 +/- 9.77 ng h/mL, AUC(0-infinity) was 55.4 +/- 8.44, and half-life (T(1/2)) was 16.2 hours. CONCLUSIONS: At doses between 15 and 165 microg, DN-101 exhibits linear pharmacokinetics. At 165 microg, DN-101 achieves systemic exposure that is 5- to 8-fold higher than that achieved with commercial formulations of calcitriol, which makes DN-101 comparable to that required for antitumor activity in vivo in a murine squamous cell carcinoma model.

Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer.

PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol (Rocaltrol, Roche Pharmaceuticals, Basel, Switzerland) and docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) in patients with metastatic androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Thirty-seven patients were treated with oral calcitriol (0.5 micro g/kg) on day 1 followed by docetaxel (36 mg/m(2)) on day 2, repeated weekly for 6 weeks of an 8-week cycle. Patients maintained a reduced calcium diet and increased oral hydration. Prostate-specific antigen (PSA) response was the primary end point, which was defined as a 50% reduction in PSA level confirmed 4 weeks later. RESULTS: Thirty of 37 patients (81%; 95% confidence interval [CI], 68% to 94%) achieved a PSA response. Twenty-two patients (59%; 95% CI, 43% to 75%) had a confirmed > 75% reduction in PSA. Eight of the 15 patients with measurable disease (53%; 95% CI, 27% to 79%) had a confirmed partial response. Median time to progression was 11.4 months (95% CI, 8.7 to 14 months), and median survival was 19.5 months (95% CI, 15.3 months to incalculable). Overall survival at 1 year was 89% (95% CI, 74% to 95%). Treatment-related toxicity was generally similar to that expected with single-agent docetaxel. Pharmacokinetics of either calcitriol or docetaxel were not affected by the presence of its companion drug in an exploratory substudy. CONCLUSION: The combination of weekly oral high-dose calcitriol and weekly docetaxel is a well-tolerated regimen for AIPC. PSA and measurable disease response rates as well as time to progression and survival are promising when compared with contemporary phase II studies of single-agent docetaxel in AIPC. Further study of this regimen is warranted.

Randomized study of high-dose pulse calcitriol or placebo prior to radical prostatectomy.

BACKGROUND: Cancer chemoprevention trials require enormous resources due to the large numbers of patients and the years of follow-up needed to achieve sufficient statistical power. Examination of candidate prevention agents using biomarkers as surrogate end points has been proposed as a method to rapidly identify promising agents for prevention trials. Treatment of patients with candidate agents prior to scheduled biopsy or surgical resection of malignancy allows for direct examination of the treatment effects on tumor tissue. In this study, we selected this approach to test several hypotheses about the effect of calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D, on early-stage human prostate cancer. METHODS: After selection of surgical treatment for histologically confirmed adenocarcinoma of the prostate, patients were randomized to either calcitriol 0.5 mug/kg or placebo weekly for 4 weeks. The expression levels of the vitamin D receptor (VDR), proliferating cell nuclear antigen, PTEN (MMAC1/TEP1), c-Myc, transforming growth factor (TGF) beta receptor type II (TGFbeta RII), and Bcl-2 were quantified using immunohistochemistry in the patients' prostate specimens post surgery. RESULTS: Thirty-seven of 39 prostate tumors were evaluable for molecular end points. VDR expression was reduced in patients treated with calcitriol (mean, 75.3% of cells) compared with those that received placebo (mean, 98.6%; P = 0.005). Calcitriol treatment did not result in a statistically significant change in the fraction of cells expressing TGFbeta RII, PTEN, or proliferating cell nuclear antigen. Bcl-2 and c-Myc expression was at the lower limits of detection in both the calcitriol group and the placebo group; therefore, we were unable to determine whether drug treatment induced a significant change in these biomarkers. CONCLUSIONS: High-dose calcitriol down-regulates VDR expression in human prostate cancer. Further study is needed to determine the biological consequences of VDR down-regulation in prostate cancer. This study shows that the use of the preprostatectomy model is feasible and can be used to test the effect of candidate chemopreventive agents on prostate cancer.

Safety and efficacy of the MDR inhibitor Incel (biricodar, VX-710) in combination with mitoxantrone and prednisone in hormone-refractory prostate cancer.

PURPOSE: VX-710 (biricodar, Incel) restores drug sensitivity to cells expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1). MRP1 is expressed in a high proportion of prostate tumors while P-gp expression is variable. Since mitoxantrone (M) and prednisone (P) are substrates for MDR transporters, we initiated a study to evaluate the safety, pharmacokinetics, and efficacy of VX-710 plus M/P in patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Eligible patients had progressive HRPC (defined as new lesions, new disease-related pain, or 50% increase in PSA within 6 weeks of entry), testosterone <30 ng/ml, no prior chemotherapy, ECOG performance status of 0-3, and adequate organ function. Patients received VX-710 (120 mg/m(2) per h) as a 72-h continuous intravenous infusion with intravenous bolus mitoxantrone (12 mg/m(2)) administered 4 h after VX-710 was started and prednisone (5 mg twice daily) administered throughout the study treatment. Endpoints included serum PSA response, PSA response duration, time to PSA progression, pain reduction, and quality of life measures. RESULTS: Enrolled in the study were 40 patients and 184 courses of VX-710 plus M/P were administered. Intensive pharmacokinetics, which were performed on six patients who received one cycle of M/P alone, followed by VX-710 plus M/P for all other cycles, showed that VX-710 did not alter mitoxantrone clearance. VX-710 blood concentration at the time of mitoxantrone administration averaged 4.52 microg/ml. VX-710 plus M/P was well tolerated. Transient nausea/vomiting and mild neutropenia were the principal treatment toxicities. Five patients experienced an uncomplicated febrile neutropenic episode (12%), three had severe nausea/vomiting, and two experienced transient moderate to severe ataxia. Of the 40 patients, 12 (30%, 95% confidence interval 16-44%) had a reduction in PSA of >/=50% and 9 of the 12 patients (23% overall, 95% CI 10-35%) achieved a reduction in PSA of >/=80% that was sustained for the duration of treatment with M/P plus VX-710. The median time to PSA progression was 41 weeks (95% CI 34-68 weeks). Of the 40 patients, 15 completed treatment with stable disease and 13 had progressive disease with increasing serum PSA during study treatment. Median survival was 48 weeks for the intent-to-treat population of 40 patients. CONCLUSIONS: The addition of VX-710 to M/P therapy did not appear to increase the proportion of patients with significant serum PSA reductions compared to M/P alone. However, the duration of PSA response observed for the 12 PSA responders suggests that MDR inhibition may benefit some patients with HRPC. In addition to MRP1 or P-gp expression, other mechanisms of drug resistance are probably associated with the relative insensitivity of HRPC to cytotoxic therapy.

A gene expression profile test to resolve head & neck squamous versus lung squamous cancers.

BACKGROUND: The differential diagnosis between metastatic head & neck squamous cell carcinomas (HNSCC) and lung squamous cell carcinomas (lung SCC) is often unresolved because the histologic appearance of these two tumor types is similar. We have developed and validated a gene expression profile test (GEP-HN-LS) that distinguishes HNSCC and lung SCC in formalin-fixed, paraffin-embedded (FFPE) specimens using a 2160-gene classification model. METHODS: The test was validated in a blinded study using a pre-specified algorithm and microarray data files for 76 metastatic or poorly-differentiated primary tumors with a known HNSCC or lung SCC diagnosis. RESULTS: The study met the primary Bayesian statistical endpoint for acceptance. Measures of test performance include overall agreement with the known diagnosis of 82.9% (95% CI, 72.5% to 90.6%), an area under the ROC curve (AUC) of 0.91 and a diagnostics odds ratio (DOR) of 23.6. HNSCC (N = 38) gave an agreement with the known diagnosis of 81.6% and lung SCC (N = 38) gave an agreement of 84.2%. Reproducibility in test results between three laboratories had a concordance of 91.7%. CONCLUSION: GEP-HN-LS can aid in resolving the important differential diagnosis between HNSCC and lung SCC tumors. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1753227817890930.

A multicenter study directly comparing the diagnostic accuracy of gene expression profiling and immunohistochemistry for primary site identification in metastatic tumors.

Metastatic tumors with an uncertain primary site can be a difficult clinical problem. In tens of thousands of patients every year, no confident diagnosis is ever issued, making standard-of-care treatment impossible. Gene expression profiling (GEP) tests currently available to analyze these difficult-to-diagnose tumors have never been directly compared with the diagnostic standard of care, immunochemistry (IHC). This prospectively conducted, blinded, multicenter study compares the diagnostic accuracy of GEP with IHC in identifying the primary site of 157 formalin-fixed paraffin-embedded specimens from metastatic tumors with known primaries, representing the 15 tissues on the GEP test panel. Four pathologists rendered diagnoses by selecting from 84 stains in 2 rounds. GEP was performed using the Pathwork Tissue of Origin Test. Overall, GEP accurately identified 89% of specimens, compared with 83% accuracy using IHC (P=0.013). In the subset of 33 poorly differentiated and undifferentiated carcinomas, GEP accuracy exceeded that of IHC (91% to 71%, P=0.023). In specimens for which pathologists rendered their final diagnosis with a single round of stains, both IHC and GEP exceeded 90% accuracy. However, when the diagnosis required a second round, IHC significantly underperformed GEP (67% to 83%, P<0.001). GEP has been validated as accurate in diagnosing the primary site in metastatic tumors. The Pathwork Tissue of Origin Test used in this study was significantly more accurate than IHC when used to identify the primary site, with the most pronounced superiority observed in specimens that required a second round of stains and in poorly differentiated and undifferentiated metastatic carcinomas.

Comparison of histopathology to gene expression profiling for the diagnosis of metastatic cancer.

BACKGROUND: Determining the primary site of metastatic cancer with confidence can be challenging. Pathologists commonly use a battery of immunohistochemical (IHC) stains to determine the primary site. Gene expression profiling (GEP) has found increasing use, particularly in the most difficult cases. In this pilot study, a direct comparison between GEP and IHC-guided methods was performed. METHODS: Ten archived formalin-fixed paraffin embedded metastatic tumor samples for which the primary site had been clinically determined were selected. Five pathologists who were blinded to the diagnosis were asked to determine the primary site using IHC and other stains selected from a panel of 84 stains. Each pathologist was provided patient sex, biopsy site and gross sample description only. Slides were digitized using ScanScope®XT at 0.25 µm/pixel. Each evaluating pathologist was allowed to provide a diagnosis in three stages: initial (after reviewing the H&E image), intermediate (after reviewing images from the first batch of stains) and final diagnosis (after the second batch of stains if requested). GEP was performed using the only FDA-cleared test for this intended use, the Pathwork Tissue of Origin Test. No sample information was provided for GEP testing except for patient sex. Results were reported as the tumor tissue type with the highest similarity score. RESULTS: In this feasibility study, GEP determined the correct primary site in 9 of the 10 cases (90%), compared to the IHC-guided method which determined the correct primary site for 32 of 50 case evaluations (average 64%, range 50% to 80%). The five pathologists directing the IHC-guided method ordered an average of 8.8 stains per case (range 1 to 18). GEP required an average of 3 slides per case (range 1 to 4). CONCLUSIONS: Results of the pilot study suggest that GEP provides correct primary site identification in a higher percentage of metastatic cases than IHC-guided methods, and uses less tissue. A larger comparative effectiveness study using this study design is needed to confirm the results. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1749854104745508.

A gene expression profile test for the differential diagnosis of ovarian versus endometrial cancers.

We have developed a gene expression profile test (Pathwork Tissue of Origin Endometrial Test) that distinguishes primary epithelial ovarian and endometrial cancers in formalin-fixed, paraffin-embedded (FFPE) specimens using a 316-gene classification model. The test was validated in a blinded study using a pre-specified algorithm and microarray files for 75 metastatic, poorly differentiated or undifferentiated specimens with a known ovarian or endometrial cancer diagnosis. Measures of test performance include a 94.7% overall agreement with the known diagnosis, an area under the ROC curve (AUC) of 0.997 and a diagnostic odds ratio (DOR) of 406. Ovarian cancers (n=30) gave an agreement of 96.7% with the known diagnosis while endometrial cancers (n=45) gave an agreement of 93.3%. In a precision study, concordance in test results was 100%. Reproducibility in test results between three laboratories was 94.3%. The Tissue of Origin Endometrial Test can aid in resolving important differential diagnostic questions in gynecologic oncology.

Potential clinical utility of gene-expression profiling in identifying tumors of uncertain origin.

AIM: To evaluate the potential impact of a gene-expression-based test on the diagnosis of primary tumors in difficult-to-diagnose cases. MATERIALS & METHODS: The Tissue of Origin Test uses 2000 gene measurements to classify the most likely primary tumor. We categorized 284 consecutive samples by pretest diagnosis, then recategorized the samples using test results to identify cases with changes in diagnosis. RESULTS: A total of 64% of incoming diagnoses were nonspecific. A leading diagnosis for the primary site was provided for remaining cases, indicating an unresolved differential. Overall, the test predicted a change in the most likely primary site, either a change from nonspecific to specific site or a change from one specific primary site to another in 81% of the cases and confirmed the suspected primary site for 15% of cases. CONCLUSION: A new molecular diagnostic has the potential to change both primary site identification and therapy selection for the majority of patients tested.

Validation and reproducibility of a microarray-based gene expression test for tumor identification in formalin-fixed, paraffin-embedded specimens.

Tumors whose primary site is challenging to diagnose represent a considerable proportion of new cancer cases. We present validation study results for a gene expression-based diagnostic test (the Pathwork Tissue of Origin Test) that aids in determining the tissue of origin using formalin-fixed, paraffin-embedded (FFPE) specimens. Microarray data files were generated for 462 metastatic, poorly differentiated, or undifferentiated FFPE tumor specimens, all of which had a reference diagnosis. The reference diagnoses were masked, and the microarray data files were analyzed using a 2000-gene classification model. The algorithm quantifies the similarity between RNA expression patterns of the study specimens and the 15 tissues on the test panel. Among the 462 specimens, overall agreement with the reference diagnosis was 89% (95% CI, 85% to 91%). In addition to the positive test results (ie, rule-ins), an average of 12 tissues for each specimen could be ruled out with >99% probability. The large size of this study increases confidence in the test results. A multisite reproducibility study showed 89.3% concordance between laboratories. The Tissue of Origin Test makes the benefits of microarray-based gene expression tests for tumor diagnosis available for use with the most common type of histology specimen (ie, FFPE).

Identification of tissue of origin in carcinoma of unknown primary with a microarray-based gene expression test.

BACKGROUND: Carcinomas of unknown primary (CUP) represent approximately 3%-5% of malignant neoplasms. Identifying the tissue of origin (TOO) in these tumors allows for more specific treatment and improves outcomes. However, primary classification remains a challenge in many cases. We evaluated the ability of a microarray-based gene expression test to identify the TOO in tumor specimens from 21 patients with a diagnosis of CUP. METHODS: The Pathwork TOO Test was used to measure gene expression patterns for 1550 genes; these were compared for similarity to patterns from 15 known tissue types. RESULTS: The TOO Test yielded a clear single positive call for the primary site in 16 of 21 (76%) specimens and was indeterminate in 5 (24%). The positive results were consistent with clinicopathologic suggestions in 10 of the 16 cases (62%). In the remaining six cases the positive results were considered plausible based on clinical information. Positive calls included colorectal (5), breast (4), ovarian (3), lung (2), and pancreas (2). The TOO Test ruled out an average of 11 primary tissues in each CUP specimen. CONCLUSION: The Pathwork TOO Test reduced diagnostic uncertainty in all CUP cases and could be a valuable addition or alternative to current diagnostic methods for classifying uncertain primary cancers.

Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue of origin.

PURPOSE: Malignancies found in unexpected locations or with poorly differentiated morphologies can pose a significant challenge for tissue of origin determination. Current histologic and imaging techniques fail to yield definitive identification of the tissue of origin in a significant number of cases. The aim of this study was to validate a predefined 1,550-gene expression profile for this purpose. METHODS: Four institutions processed 547 frozen specimens representing 15 tissues of origin using oligonucleotide microarrays. Half of the specimens were metastatic tumors, with the remainder being poorly differentiated and undifferentiated primary cancers chosen to resemble those that present as a clinical challenge. RESULTS: In this blinded multicenter validation study the 1,550-gene expression profile was highly informative in tissue determination. The study found overall sensitivity (positive percent agreement with reference diagnosis) of 87.8% (95% CI, 84.7% to 90.4%) and overall specificity (negative percent agreement with reference diagnosis) of 99.4% (95% CI, 98.3% to 99.9%). Performance within the subgroup of metastatic tumors (n = 258) was found to be slightly lower than that of the poorly differentiated and undifferentiated primary tumor subgroup, 84.5% and 90.7%, respectively (P = .04). Differences between individual laboratories were not statistically significant. CONCLUSION: This study represents the first adequately sized, multicenter validation of a gene-expression profile for tissue of origin determination restricted to poorly differentiated and undifferentiated primary cancers and metastatic tumors. These results indicate that this profile should be a valuable addition or alternative to currently available diagnostic methods for the evaluation of uncertain primary cancers.

Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel.

BACKGROUND: Survival in patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer (AIPC) is improved with 10 to 12 cycles of docetaxel-containing chemotherapy but further management is undefined. In the current study, the authors examined retreatment with the same regimen after a treatment holiday. METHODS: Patients treated with docetaxel at a dose of 36 mg/m(2) plus either high-dose calcitriol (DN-101; 45 mug) or placebo administered weekly for 3 of every 4 weeks could suspend treatment if their serum prostate-specific antigen (PSA) level was reduced >or=50% and reached a level or=50% and was >or=2 ng/mL or when there was other evidence of disease progression. The study was not powered to compare treatment holiday outcomes between the 2 arms. RESULTS: A total of 250 patients were randomized 1:1. Overall, 18% of patients (20% in the high-dose calcitriol group and 16% in the placebo group) entered the intermittent chemotherapy arm. The median duration of the first chemotherapy holiday was 18 weeks (range, 4%70 weeks). On resumption of treatment after the first holiday, 45.5% of evaluable patients responded with a >or=50% reduction in serum PSA from their postholiday baseline, 45.5% met the criteria for stable PSA for at least 12 weeks, and 9.1% of patients developed disease progression. CONCLUSIONS: To the authors' knowledge, the current study is the first report of intermittent chemotherapy in patients with AIPC who were prospectively tested in a large multi-institutional trial. This strategy results in a clinically significant duration of chemotherapy holidays and can be offered to a minority of patients. At the time of retreatment, the majority of patients again respond to treatment or their PSA levels stabilized. Additional studies of intermittent chemotherapy are needed to better characterize the optimal patient population and the optimal approach.

Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators.

PURPOSE: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel. PATIENTS AND METHODS: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. RESULTS: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%). CONCLUSION: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma.

BACKGROUND: In preclinical systems, calcitriol, the natural vitamin D receptor (VDR) ligand, has been found to demonstrate antiproliferative effects, although concentrations > 1 nM are required. Unlike daily dosing, weekly administration of oral calcitriol can safely achieve such blood calcitriol concentrations. This study sought to define the long-term toxicity of this regimen and measure its effect on serum prostate specific antigen (PSA) levels in patients with hormone-naïve prostate carcinoma. METHODS: Patients with a rising serum PSA after prostatectomy and/or radiation and no prior systemic therapy for prostate carcinoma recurrence maintained a reduced calcium diet and received calcitriol 0.5 microg/kg orally once each week until a maximum of a four-fold increase in the PSA. RESULTS: Twenty-two patients received treatment for a median of 10 months (range, 2-25+ months). Treatment was well tolerated with no Grade >or= 3 toxicity and no hypercalcemia or renal calculi. No patient had a PSA response (50% reduction confirmed 4 weeks later). Three patients (14%, 95% CI 0-28%) had confirmed reductions in the PSA ranging from 10% to 47%. Statistically significant increases in the PSA doubling time (PSADT) were seen in three additional patients and no patient had a shorter PSADT after starting treatment. For the entire study population, the median PSADT increased from 7.8 months to 10.3 months (P = 0.03 by Wilcoxon signed rank test). CONCLUSIONS: Weekly high-dose calcitriol was found to be safe. The primary efficacy endpoint of 50% reduction in the serum PSA was not achieved with this therapy. Randomized studies are needed to further examine the impact of this therapy on prostate carcinoma progression.