National Cancer Institute Trial Research Articles

Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer

Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater). To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers. RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023. Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy. Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily. Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater. In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.

An evaluation of trends in the representation of patients by age, sex, and diverse race/ethnic groups in bladder and kidney cancer clinical trials.

To determine the representation of women, minorities, and the elderly groups in clinical trials and whether participation has changed over time. Retrospective study in the National Cancer Institute (NCI) Clinical Data Update System and Center for Disease Control and Prevention United States Cancer Statistics 2000 to 2019. We compared cancer incidence proportion to proportion of patients enrolled in an NCI trial when stratified by race/ethnicity, sex, and age. We performed multivariable analysis to determine the odds of participating in a clinical trial in 2015 to 2019 when compared to 2000 to 2004. This study included 14,094 patients, 12,169 (86.3%) non-Hispanic White patients, 662 (4.7%) Black patients, and 660 (4.7%) Hispanic patients. There were 3,701 (26.3%) female patients and 10,393 (73.7%) male patients. For bladder cancer clinical trials, Black patients and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.57-0.88, P = 0.002) and (OR 0.69, 95%CI 0.54-0.88, P = 0.003), respectively. For kidney cancer trials, Black and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (OR 0.42, OR 0.33-0.54, P < 0.001) and (OR 0.68, 95% CI 0.55-0.83, P < 0.001), respectively. Women were underrepresented in kidney cancer trials compared to men (OR 0.80, 95% CI 0.72-0.89) and similarly for bladder cancer trials (OR 0.72, 95% CI 0.64-0.81, P < 0.001). For bladder cancer trials, the participation of Black patients over time (OR 1.04, P = 0.814) and female patients over time (OR 1.03, P = 0.741) were unchanged. For kidney cancer trials, the participation of Black patients over time (OR 1.17, P = 0.293) and female patients over time (OR 1.03, P = 0.663) participation was also unchanged. In this study of clinical trials in bladder and kidney cancer, we identified that Blacks, Hispanics, and females were underrepresented. Additionally, Black and female participation was unchanged over the span of 20 years.

The Multiple Myeloma Research Consortium (MMRC): A Model For Accelerating Development Of Novel Therapies For Multiple Myeloma

The Multiple Myeloma Research Consortium (MMRC): A Model For Accelerating Development Of Novel Therapies For Multiple Myeloma

Adjuvant and Neoadjuvant Radiation Therapy for Locally Advanced Bladder Cancer

Local-regional failure for patients with ≥pT3 urothelial carcinoma after radical cystectomy is a significant clinical challenge. Prospective randomised trials have failed to show that chemotherapy reduces the risk of local-regional recurrences. Salvage treatment for local failures is difficult and often unsuccessful. There is promising evidence, particularly from a recent Egyptian National Cancer Institute trial, that radiation therapy plus chemotherapy can significantly reduce local recurrences compared with chemotherapy alone, and that this improvement in local-regional control may translate to meaningful improvements in disease-free and overall survival with acceptable toxicity. In light of the high rates of local failure following cystectomy for locally advanced disease and the progress that has been made in identifying patients at high risk of failure and the patterns of failure in the pelvis, the National Comprehensive Cancer Network guidelines were revised to include postoperative radiotherapy as an option to consider for patients with ≥pT3 disease. Here we review the problem of local-regional failure after cystectomy, identify patients who would probably benefit from adjuvant radiotherapy, review the patterns of pelvic failure after cystectomy, discuss technical details of radiation treatment and review the modern literature on this topic. Adjuvant radiotherapy should be considered as a treatment option for patients with locally advanced disease, especially those with positive margins or squamous cell carcinoma.

Abstract P4-10-04: Assessment of clinical trial participation on breast cancer survival

Abstract Background Accredited cancer treatment centers offer clinical trials for patients since it is universally accepted that participation in these trials is advantageous. Purpose The purpose of this study was to assess whether clinical trial participation was associated with a survival advantage. Methods We identified 308,291 cases of first primary female invasive breast cancer from the California Cancer Registry 2000-2015. Participation in a clinical trial was documented. Clinical trials were defined as National Cancer Institute (NCI) sponsored studies such as National Surgical Adjuvant Breast and Bowel Project (NSABP) and Southwest Oncology Group (SWOG); pharmaceutical trials; and local investigator initiated studies. The distribution of age, race/ethnicity, socioeconomic status (SES), and stage between clinical trial participants and non-participants was compared using contingency tables and the χ2 Test. Kaplan-Meier Survival Analysis and the Log Rank test were used to compare differences in breast cancer specific survival between participants and non-participants. Cox Regression Analysis was used to estimate the risk of mortality between participants and non-participants after adjusting for age, race/ethnicity, SES, grade, and treatment. Analyses were conducted separately for each stage. Hazard ratios (HR) and 95% confidence intervals (CIs) were reported. Results There were 3,517 (1.1%) patients who participated in a clinical trial. Almost 50% of participants were enrolled in an NCI trial, 38% in a local/investigator initiated study, and 13% were in a trial sponsored by a pharmaceutical company. Trial participation was highest for patients less than 45 years of age (21.9%) and lowest in patients 70 years of age and older (12.3%). Most participants were in stage 2 (44.6%). Participation increased with increasing SES. Only 8.5% of participants were in the lowest SES whereas 35.4% were in the highest SES. Unadjusted survival analysis indicated that there was no survival advantage for stage 1 patients (χ2 = 0.41, p=0.52) whereas study participants in stages 2, 3, and 4 had statistically significantly better survival. Adjusted hazard ratios indicated that stage 2 patients participating in a trial had a 23% reduced risk of mortality (HR=0.77; CI: 0.65 - 0.94). For patients in stage 4, the risk of mortality was reduced by 36% (HR=0.64; CI: 0.47 - 0.87). There was no risk reduction for patients in stages 1 and 3. Conclusion Only a small percent of patients enroll in breast cancer clinical trials and participation is correlated with age and SES. There is a survival advantage for participation in a clinical trial for stages 2 and 4 patients. Citation Format: Parise C, Caggiano V. Assessment of clinical trial participation on breast cancer survival [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-04.

‘Optimism bias’ in contemporary national clinical trial network phase III trials: are we improving?

BackgroundPrevious studies have found that overestimating treatment effects (i.e. ‘optimism bias’) leads to underpowered clinical trials. The prevalence of ‘optimism bias’ in contemporary National Clinical Trials Network (NCTN) cancer clinical trials is unknown. MethodsWe conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized versus observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided. ResultsWe identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary end point favoring the experimental treatment. The median ratio of observed-to-expected hazard ratios among trials that observed a statistically significant effect on the primary end point was 1.07 (range: 0.33–1.28) versus 1.32 (range: 0.86–2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 and 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared with 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol. ConclusionsDespite a reduction in ‘optimism bias’ compared with previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed.

Meeting the Challenge: The National Cancer Institute's Central Institutional Review Board for Multi-Site Research.

The National Institutes of Health (NIH) issued a new policy that requires a single institutional review board (IRB) of record be used for all protocols funded by the NIH that are carried out at more than one site in the United States, effective January 2018. This policy affects several hundred clinical trials opened annually across the NIH. Limited data exist to compare the use of a single IRB to that of multiple local IRBs, so some institutions are resistant to or distrustful of single IRBs. Since 2001, the National Cancer Institute (NCI) has funded a central IRB (CIRB) that provides human patient reviews for its extensive national cancer clinical trials program. This paper presents data to show the adoption, efficiencies gained, and satisfaction of the CIRB among NCI trial networks and reviews key lessons gleaned from 16 years of experience that may be informative for others charged with implementation of the new NIH single-IRB policy.

Modification and validation of an analytical source model for external beam radiotherapy Monte Carlo dose calculations.

A dose calculation tool, which combines the accuracy of the dose planning method (DPM) Monte Carlo code and the versatility of a practical analytical multisource model, which was previously reported has been improved and validated for the Varian 6 and 10 MV linear accelerators (linacs). The calculation tool can be used to calculate doses in advanced clinical application studies. One shortcoming of current clinical trials that report dose from patient plans is the lack of a standardized dose calculation methodology. Because commercial treatment planning systems (TPSs) have their own dose calculation algorithms and the clinical trial participant who uses these systems is responsible for commissioning the beam model, variation exists in the reported calculated dose distributions. Today's modern linac is manufactured to tight specifications so that variability within a linac model is quite low. The expectation is that a single dose calculation tool for a specific linac model can be used to accurately recalculate dose from patient plans that have been submitted to the clinical trial community from any institution. The calculation tool would provide for a more meaningful outcome analysis. The analytical source model was described by a primary point source, a secondary extra-focal source, and a contaminant electron source. Off-axis energy softening and fluence effects were also included. The additions of hyperbolic functions have been incorporated into the model to correct for the changes in output and in electron contamination with field size. A multileaf collimator (MLC) model is included to facilitate phantom and patient dose calculations. An offset to the MLC leaf positions was used to correct for the rudimentary assumed primary point source. Dose calculations of the depth dose and profiles for field sizes 4 × 4 to 40 × 40 cm agree with measurement within 2% of the maximum dose or 2 mm distance to agreement (DTA) for 95% of the data points tested. The model was capable of predicting the depth of the maximum dose within 1 mm. Anthropomorphic phantom benchmark testing of modulated and patterned MLCs treatment plans showed agreement to measurement within 3% in target regions using thermoluminescent dosimeters (TLD). Using radiochromic film normalized to TLD, a gamma criteria of 3% of maximum dose and 2 mm DTA was applied with a pass rate of least 85% in the high dose, high gradient, and low dose regions. Finally, recalculations of patient plans using DPM showed good agreement relative to a commercial TPS when comparing dose volume histograms and 2D dose distributions. A unique analytical source model coupled to the dose planning method Monte Carlo dose calculation code has been modified and validated using basic beam data and anthropomorphic phantom measurement. While this tool can be applied in general use for a particular linac model, specifically it was developed to provide a singular methodology to independently assess treatment plan dose distributions from those clinical institutions participating in National Cancer Institute trials.

TU‐G‐BRD‐05: Results From Multi‐Institutional Measurements with An Anthropomorphic Spine Phantom

Purpose:To analyze the results from an anthropomorphic spine phantom used for credentialing institutions for National Cancer Institute (NCI) sponsored clinical trial.Methods:An anthropomorphic phantom that contains left and right lungs, a heart, an esophagus, spinal cord, bony material and a PTV was sent to institutions wishing to be credentialed for NCI trials. The PTV holds 4 TLD and radiochromic film in the axial and sagittal planes. The heart holds one TLD. Institutions created IMRT plans to cover ≥90% of the PTV with 6 Gy and limit the cord dose to &lt;0.35cc receiving 3.75 Gy and &lt;1.2cc receiving 2.63 Gy. They were instructed to treat the phantom as they would a patient, including making plan specific IMRT/SBRT QA measurements before treatment. The TLD results in the PTV were required to be within ±7% of the plan dose. A gamma calculation was performed using the film results and the submitted DICOM plan. ≥85% of the analyzed region was required to pass a 5%/3 mm criteria.Results:176 institutions irradiated the spine phantom for a total of 255 results. The pass rate was 73% (187 irradiations) overall. 44 irradiations failed only the gamma criteria, 2 failed only the dose criteria and 22 failed both. The most used planning systems were Eclipse (116) and Pinnacle (52) and they had pass rates of 76% and 71%, respectively. The AAA algorithm had a pass rate of 77% while superposition type algorithms had a 71% pass rate. The average TLD measurement to institution calculation ratio was 0.99 (0.04 std dev.). The average percent pixels passing the gamma criteria for films was 89% (12% std dev.)Conclusion:Results show that this phantom is an important part of credentialing and that we have room for improvement in IMRT/SBRT spine treatments.This work was supported by PHS CA180803 and CA037422 awarded by NCI, DHHS.

Radiation Therapy for Extremity Soft Tissue Sarcoma: In the Absence of a Clear Survival Benefit, Why Do We Give It?

Due in large part to several sentinel contributions from the National Cancer Institute (NCI), the local management of extremity soft tissue sarcoma (ESTS) today typically results in excellent local control and very good limb function. In 1982, Rosenberg et al. showed equivalent 5-year survival rates for limb-sparing surgery (LSS) plus radiation therapy (RT) compared with amputation and an acceptable 15 % local recurrence (LR) rate for LSS plus RT. Following publication of this landmark trial, amputation rates appropriately plummeted. In 1998, Yang et al. reported results from a second NCI randomized trial that compared LSS plus RT with LSS alone and showed a clear significant local control benefit for RT for both highand low-grade ESTS. A randomized trial from Memorial Sloan-Kettering Cancer Center (MSKCC) in 1996 affirmed the local control advantage for RT (in the form of brachytherapy) in addition to LSS. Several nonrandomized series have reported LR rates\15 % for LSS alone without RT, but others have shown unacceptably high rates of LR with this approach. Given the conflicting results for surgery alone from nonrandomized reports, and the clear local control advantage with RT demonstrated by randomized trials, the standard of care for most high-grade ESTS is LSS plus RT. The main and undisputed benefit of adjuvant RT is improved local control, and local control rates for LSS plus RT are\15 % in modern series. However, the effect of RT on overall survival is ambiguous. The aforementioned randomized trials as well as the 20-year update of the NCI trial reported by Beane et al. that accompanies this editorial, fail to show a statistically significant difference in survival with the addition of RT. Since RT has its own treatment-related toxicities and is not associated with an improvement in overall survival, should we stop using RT in conjunction with LSS? The report by Beane et al. shows a trend toward higher 20-year survival rates for LSS plus RT compared with LSS alone (71 vs. 64 %, p = 0.22). As the authors point out, this study was only powered to detect a 21 % survival difference. On the other hand, a review of 6,960 patients with high-grade ESTS showed a statistically significant improved 3-year survival rate of 73 % for LSS plus RT compared with 63 % for LSS alone (p 0.001). It is quite possible that adjuvant RT for ESTS does in fact confer a statistically significant survival advantage, but due to small patient numbers in most series, such a benefit has not been reliably demonstrated. This was the case for breast cancer. Most individual trials failed to show a significant association between local control and survival. Nevertheless, patients with breast cancer were still treated with RT because of the local control advantage it conferred. Ultimately, a meta-analysis of 42,000 patients demonstrated a clear link between improved local control and superior survival. Another potential benefit of adjuvant RT relates to the consequences of a LR. The development of a LR necessitates further surgery or surgeries and possible RT, and it may result in greater long-term toxicity than if RT had been delivered after the first definitive resection. In addition, development of a LR can have a devastating psychological impact. On the other hand, delivery of adjuvant RT is associated with toxicities, the severity of which must be factored into Society of Surgical Oncology 2014

A surveillance system for monitoring, public reporting, and improving minority access to cancer clinical trials.

The Institute of Medicine (IOM) has recommended that each person with cancer should have access to clinical trials, which have been associated with improving care quality and disparities. With no effective enrollment monitoring system, patterns of trial enrollment remain unclear. We developed a population-based, statewide system designed to facilitate monitoring of cancer trial enrollment and targeting of future interventions to improve it. Person-level cancer incidence data from the North Carolina Central Cancer Registry (NCCCR), person-level treatment trial accrual data from the National Cancer Institute (NCI), and county-level Area Resource Files (ARF) measures for 12 years, 1996-2007, were studied. Deidentified person-level data necessitated county-level analysis. Enrollment rates were estimated as the ratio of trial enrollment to cancer incidence for each race, gender, year, and county combination. Multivariable analysis examined factors associated with trial accrual. Sensitivity analyses examined spurious fluctuations and temporal discordance of incidence and enrollment. The NCI treatment trial enrollment rate was 2.39% for whites and 2.20% for minorities from 1996 to 2007, and 2.88% and 2.47%, respectively, from 2005 to 2007. Numerous counties had no minority enrollment. The 2005-2007 enrollment rates for white and minority females was 4.04% and 3.59%, respectively, and for white and minority males was 1.74% and 1.36%, respectively. Counties with a medical school or NCI Community Clinical Oncology Program (CCOP)-affiliated practice had higher trial enrollment. We examined NCI trial accrual only - industry-sponsored and investigator-initiated trials were excluded; however, studies comprise the majority of all clinical trial participants. Delays in data availability may hinder the immediacy of population-based analyses. Model stability and consistency suggest that this system is effective for population-based enrollment surveillance. For North Carolina, it suggests a worsening disparity in minority trial enrollment, though our analyses elucidate targets for intervention. Regional enrollment variation suggests the importance of access to clinical research networks and infrastructure. Substantial gender differences merit further examination.

Utility of oncotype DX risk estimates in clinically intermediate risk hormone receptor‐positive, HER2‐normal, grade II, lymph node‐negative breast cancers

Oncotype DX breast cancer assay (Genomic Health, Redwood City, Calif) stratifies patients with early breast cancer according to risk of distant recurrence. The authors hypothesized that the test is ordered when clinicopathological variables yield equivocal risk estimates. The current study also showed how often the test clarifies clinically ambiguous risk status. The authors examined clinical/pathological characteristics and calculated risk of recurrence with Adjuvant! for 309 consecutive patients who underwent Oncotype DX testing at M. D. Anderson Cancer Center. Of the patients comprising this study, most had stage I/II (n = 306, 99%) and grade I/II tumors (n = 236, 76%). The median risk of recurrence by Adjuvant! was 16% (IQR 11.2 to 20.4). Oncotype DX stratified 52% (n = 160), 40% (n = 122) and 9% (n = 27) of this clinically intermediate risk population into low, intermediate, and high risk groups, respectively. Correlation between projected risk of recurrence by Adjuvant! (Adjuvant!, online software and website) and Oncotype DX was minimal (r = 0.13). Recurrence score (P < .0001), but not age or tumor size, was higher in patients who received adjuvant chemotherapy. In all 3 grade subsets, recurrence score was higher in those who received chemotherapy compared with those who did not (P = .02, P < .0001, and P = .0009, respectively). All lobular carcinomas (n = 40) were classified as low/intermediate risk. Oncotype DX yielded potentially informative risk assignments in patients considered indeterminate risk by routine clinical variables. However, 40% of the time test results reflected intermediate risk, with widely used recurrence score thresholds. This proportion increased to 66% using revised thresholds implemented by National Cancer Institute's Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx.

Imaging in drug development: will it deliver on the promise of personalised medicine?

Over recent years, many new techniques have been applied to drug development in an effort to provide safer and more effective therapies to the patient. In addition, the intense competition between commercial interests continues to drive this search for new and effective technologies. The common goal is the provision of personalised medicine: an approach based on our growing understanding of the molecular basis of disease.

Commentary: Timing Is Everything

Commentary: Timing Is Everything

Differences in Clinical Trial Patient Attributes and Outcomes According to Enrollment Setting

During the last 25 years, National Cancer Institute (NCI) cooperative trial groups have extended trial networks from academic centers to include certain community and Veterans Health Administration (VHA) centers. We compared trial patients' attributes and outcomes by these enrollment settings. Studying 2,708 patients on one of 10 cooperative group, randomized lung trials at 272 institutions, we compared patient attributes by enrollment setting (ie, academic, community, and VHA affiliates). We used adjusted Cox regression to evaluate for survival differences by setting. Main member institutions enrolled 44% of patients; community affiliates enrolled 44%; and VHAs enrolled 12%. Patient attributes (ie, case-mix) of age, ethnicity, sex, and performance status varied by enrollment setting. After analysis was adjusted for patient case-mix, no mortality differences by enrollment setting were noted. Although trial patients with primarily advanced-stage lung cancer from nonacademic centers were older and had worse performance statuses than those from academic centers, survival did not differ by enrollment setting after analysis accounted for patient heterogeneity. An answer for whether long-term outcomes for patients at community and VHA centers affiliated with cooperative trial groups are equivalent to those at academic centers when care is delivered through NCI trials requires additional research among patients with longer survival horizons.

Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862)

AbstractBACKGROUND:This phase 2 trial was designed to evaluate the efficacy of vorinostat in chemotherapy‐pretreated patients with metastatic castration‐resistant prostate cancer.METHODS:Patients with disease progression on 1 prior chemotherapy, a prostate‐specific antigen (PSA) ≥5 ng/mL, and adequate organ function were treated with 400 mg vorinostat orally daily. The primary endpoint was the 6‐month progression rate. Secondary endpoints included safety, rate of PSA decline, objective response, overall survival, and effects of vorinostat on serum interleukin‐6 (IL‐6) levels.RESULTS:Twenty‐seven eligible patients were accrued. The median number of cycles delivered was 2 (range, 1‐7). All patients were taken off therapy before 6 months. The best objective response in the eligible patient was stable disease in 2 (7%) patients. No PSA decline of ≥50% was observed. There was 1 grade 4 adverse event (AE), and 44% of patients experienced grade 3 adverse events. The most common adverse events were fatigue (81%), nausea (74%), anorexia (59%), vomiting (33%), diarrhea (33%), and weight loss (26%). Median time to progression and overall survival were 2.8 and 11.7 months, respectively. Median IL‐6 levels (pg/mL) were higher in patients removed from the protocol for toxicity compared with progression at all time points, including baseline (5.2 vs 2.1, P = .02), Day 15 Cycle 1 (9.5 vs 2.2, P = .01), Day 1 Cycle 2 (9.8 vs 2.2, P = .01), and end of study (11.0 vs 2.9, P = .09).CONCLUSIONS:Vorinostat at this dose was associated with significant toxicities limiting efficacy assessment in this patient population. The significant association between IL‐6 levels and removal from the study for toxicities warrants further investigation. Cancer 2009. © 2009 American Cancer Society.

Initial clinical experience with real‐time transrectal ultrasonography‐magnetic resonance imaging fusion‐guided prostate biopsy

To evaluate the feasibility and utility of registration and fusion of real-time transrectal ultrasonography (TRUS) and previously acquired magnetic resonance imaging (MRI) to guide prostate biopsies. Two National Cancer Institute trials allowed MRI-guided (with or with no US fusion) prostate biopsies during placement of fiducial markers. Fiducial markers were used to guide patient set-up for daily external beam radiation therapy. The eligible patients had biopsy-confirmed prostate cancer that was visible on MRI. A high-field (3T) MRI was performed with an endorectal coil in place. After moving to an US suite, the patient then underwent TRUS to visualize the prostate. The US transducer was equipped with a commercial needle guide and custom modified with two embedded miniature orthogonal five-degrees of freedom sensors to enable spatial tracking and registration with MR images in six degrees of freedom. The MRI sequence of choice was registered manually to the US using custom software for real-time navigation and feedback. The interface displayed the actual and projected needle pathways superimposed upon the real-time US blended with the prior MR images, with position data updating in real time at 10 frames per second. The registered MRI information blended to the real-time US was available to the physician who performed targeted biopsies of highly suspicious areas. Five patients underwent limited focal biopsy and fiducial marker placement with real-time TRUS-MRI fusion. The Gleason scores at the time of enrollment on study were 8, 7, 9, 9, and 6. Of the 11 targeted biopsies, eight showed prostate cancer. Positive biopsies were found in all patients. The entire TRUS procedure, with fusion, took approximately 10 min. The fusion of real-time TRUS and prior MR images of the prostate is feasible and enables MRI-guided interventions (like prostate biopsy) outside of the MRI suite. The technique allows for navigation within dynamic contrast-enhanced maps, or T2-weighted or MR spectroscopy images. This technique is a rapid way to facilitate MRI-guided prostate therapies such as external beam radiation therapy, brachytherapy, cryoablation, high-intensity focused ultrasound ablation, or direct injection of agents, without the cost, throughput, or equipment compatibility issues that might arise with MRI-guided interventions inside the MRI suite.

Adverse Event Reporting in Publications Compared With Sponsor Database for Cancer Clinical Trials

Prospectively planned collection and analysis of adverse event (AE) data are essential parts of well-conducted clinical trials. The AE data in a trial sponsor's database should be comparable with what is stipulated in the protocol and with the AE data published. We examined whether the published AE data differ from those in the sponsor's database and from the data collection requirements stated in study protocols. We searched the National Cancer Institute (NCI) Clinical Data Update System (CDUS) for studies that used the Common Toxicity Criteria version 2.0 and for which a final study publication was available. We extracted from the protocols information pertaining to AE collection and reporting methods and compared it with the methods cited in the article. We also compared the AE data in the trial publication with the AE data submitted by the investigators to CDUS. We identified 22 studies meeting the criteria for this review. There was considerable inconsistency between AE collection and reporting methods cited in the protocols versus final publications. AE data in the article and CDUS were not identical. Twenty-seven percent of article high-grade AEs could not be matched to agent-attributable AEs in the CDUS. Twenty-eight percent of CDUS high-grade AEs could not be matched to AEs in the corresponding article. In 14 of 22 articles, the number of high-grade AEs in CDUS differed from the number in the articles by 20% or more. Lack of consistency in and reporting of AEs are associated with NCI database and trial publication AE data discrepancy.

Phase II Evaluations of Cilengitide in Asymptomatic Patients with Androgen-Independent Prostate Cancer: Scientific Rationale and Study Design

Two randomized trials demonstrated an improvement in survival with docetaxel-based chemotherapy for patients with metastatic, androgenindependent prostate disease. However, the effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential. Cilengitide (EMD121974; NSC 707544), is a potent selective αvβ3 and αvβ5 integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities including endothelial cell proliferation and migration. Blocking the ligation of integrins by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In prostate cancer specifically, integrins are known to be involved in metastases with differential expression on tumor cells. Tumors and vascular endothelial cells produce factors, such as vascular endothelial growth factor and basic fibroblast growth factor, that promote neovascularization, which has been implicated in prostate cancer progression. Cilengitide has been shown to inhibit αvβ3- and αvβ5-mediated cell adhesion and block in vitro endothelial cell migration. In vivo experiments demonstrated that cilengitide inhibited cytokine-induced basic fibroblast growth factor– and vascular endothelial growth factor–mediated angiogenesis in a dose-dependent manner. Cilengitide also inhibited tumor growth in various in vivo systems. Two Cancer Therapy Evaluation Program–sponsored, multicenter, phase II trials are designed to evaluate the safety and efficacy of this agent in patients with androgen-independent prostate cancer. National Cancer Institute trial 6735 is evaluating cilengitide at 2000 mg in patients with nonmetastatic androgen-independent prostate cancer, and National Cancer Institute trial 6372 is evaluating 2 dose levels of cilengitide, 500 mg or 2000 mg, intravenously twice weekly in patients with metastatic prostate cancer.

Valdecoxib Withdrawal Leaves Pain Relief Treatment Gap

Valdecoxib Withdrawal Leaves Pain Relief Treatment Gap