National Cancer Institute Cooperative Research Articles

Deep myeloid cell profiling provides new insights into modulators of CAR T cell expansion in patients with pediatric solid tumors

Abstract Chimeric antigen receptor (CAR) T cells have shown remarkable results in hematological malignancies but limited efficacy in the setting of solid tumors. As myeloid-mediated immune suppression is known to play an important role in dampening antitumor activity, we hypothesized that myeloid cells impact CAR T cell expansion in patients with solid tumors. A phase I trial (NCT02107963) was performed to determine the feasibility and safety of administering 3rd generation GD2-CAR (GD2-CAR.OX40.28.z.ICD9) T cells in children and young adults with neuroblastoma and osteosarcoma. 76.9% of patients had stable disease by day 28, eventually all patients had disease progression. We stratified patients based on good versus poor CAR T cell expansion and evaluated peripheral immune profiles pre- and post-treatment by qPCR, ELISA, CyTOF, ATAC-seq, and RNA-seq. While A higher proportion of monocytes in pre-treatment apheresis was associated with poor CAR T cell expansion and CXCR3 expression on monocytes was the most robust marker of good CAR T cell expansion in this cohort. Longitudinal analysis demonstrated that CXCR3+ monocytes were low following treatment in both good and poor CAR T cell expanders, demonstrating a transition in myeloid populations in response to GD2-CAR T cell treatment. Together, these data suggest that GD2-CAR T cell administration is associated with changes in the myeloid cell compartment. This study provides evidence of novel myeloid-based pre-treatment biomarkers of CAR T cell expansion and rationale for the combination of CAR T cells with myeloid-modulating therapies as a strategy to improve outcomes for patients with solid tumors. Clinical trial supported in part by: Intramural Research Program, National Cancer Institute, NIH Clinical Center, National Institutes of Health. Scientific and financial support for the CIMAC-CIDC Network are provided through the National Cancer Institute (NCI) Cooperative Agreements: U24CA224331 (to the Dana-Farber Cancer Institute CIMAC), U24CA224309 (to the Stanford University CIMAC), and U24CA224316 (to the CIDC at Dana-Farber Cancer Institute). Scientific and financial support for the Partnership for Accelerating Cancer Therapies (PACT) public-private partnership (PPP).

TAILORx Update

TAILORx Update

Clinical Trials in Thoracic Surgery: A Report From Ginsberg Day 2017 and Early Risers at STS 2017

No unified source lists clinical trials relevant to general thoracic surgery. This description summarizes the current offerings across the National Cancer Institute Cooperative Group-sponsored clinical trials, and includes trials involving surgery for lung cancer and esophageal cancer, and in some instances, perioperative management of patients undergoing thoracic surgery.

Pooled Analysis of Individual Patient Data on Concurrent Chemoradiotherapy for Stage III Non-Small-Cell Lung Cancer in Elderly Patients Compared With Younger Patients Who Participated in US National Cancer Institute Cooperative Group Studies.

Purpose Concurrent chemoradiotherapy is standard treatment for patients with stage III non-small-cell lung cancer. Elderly patients may experience increased rates of adverse events (AEs) or less benefit from concurrent chemoradiotherapy. Patients and Methods Individual patient data were collected from 16 phase II or III trials conducted by US National Cancer Institute-supported cooperative groups of concurrent chemoradiotherapy alone or with consolidation or induction chemotherapy for stage III non-small-cell lung cancer from 1990 to 2012. Overall survival (OS), progression-free survival, and AEs were compared between patients age ≥ 70 (elderly) and those younger than 70 years (younger). Unadjusted and adjusted hazard ratios (HRs) for survival time and CIs were estimated by single-predictor and multivariable frailty Cox models. Unadjusted and adjusted odds ratio (ORs) for AEs and CIs were obtained from single-predictor and multivariable generalized linear mixed-effect models. Results A total of 2,768 patients were classified as younger and 832 as elderly. In unadjusted and multivariable models, elderly patients had worse OS (HR, 1.20; 95% CI, 1.09 to 1.31 and HR, 1.17; 95% CI, 1.07 to 1.29, respectively). In unadjusted and multivariable models, elderly and younger patients had similar progression-free survival (HR, 1.01; 95% CI, 0.93 to 1.10 and HR, 1.00; 95% CI, 0.91 to 1.09, respectively). Elderly patients had a higher rate of grade ≥ 3 AEs in unadjusted and multivariable models (OR, 1.35; 95% CI, 1.07 to 1.70 and OR, 1.38; 95% CI, 1.10 to 1.74, respectively). Grade 5 AEs were significantly higher in elderly compared with younger patients (9% v 4%; P < .01). Fewer elderly compared with younger patients completed treatment (47% v 57%; P < .01), and more discontinued treatment because of AEs (20% v 13%; P < .01), died during treatment (7.8% v 2.9%; P < .01), and refused further treatment (5.8% v 3.9%; P = .02). Conclusion Elderly patients in concurrent chemoradiotherapy trials experienced worse OS, more toxicity, and had a higher rate of death during treatment than younger patients.

Tobacco assessment in completed lung cancer treatment trials.

An effort over 3 years to conduct a data pooling project regarding the association between smoking and lung cancer treatment outcomes has shown that, of 32 completed studies of lung cancer treatments in 1 National Cancer Institute Cooperative Group, only a minority have usable data concerning smoking‐related variables. Clinical trials research is needed to inform patients with cancer and their physicians about the impact of smoking, and how smoking cessation may affect the course of their disease.

Everolimus combined with R-CHOP-21 for new, untreated, diffuse large B-cell lymphoma (NCCTG 1085 [Alliance]): safety and efficacy results of a phase 1 and feasibility trial

The PI3K-mTORC pathway is upregulated in diffuse large B-cell lymphoma (DLBCL) and can be targeted with the mTOR complex 1 (mTORC1) inhibitor everolimus. Everolimus has activity in relapsed DLBCL. These data provide the rationale to combine everolimus with standard treatment for DLBCL of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone delivered in a 21-day cycle (R-CHOP-21) for six cycles. We did a phase 1 and feasibility study (NCCTG 1085) of oral everolimus 10 mg/day plus R-CHOP-21 in patients aged at least 18 years with new, untreated, CD20-positive DLBCL (stages II-IV) in the NCCTG (Alliance) National Cancer Institute Cooperative Group (USA). Patients received standard R-CHOP-21 (intravenous rituximab 375 mg/m(2), intravenous cyclophosphamide 750 mg/m(2), intravenous doxorubicin 50 mg/m(2), and intravenous vincristine 1·4 mg/m(2) [maximum 2·0 mg] all on day 1 of the 21-day cycle; and oral prednisone 100 mg/m(2) each day on days 1-5 of the cycle) for six cycles with scheduled subcutaneous pegfilgrastim 6 mg on day 2 of each cycle. We tested two schedules: everolimus given in the fasting state either on days 1-10 or days 1-14 of the R-CHOP cycle. The primary endpoint of the phase 1 portion of this study was to establish the maximum tolerated dose of everolimus that could be combined with R-CHOP-21. The primary endpoint of the feasibility portion of the study was to determine the feasibility of the regimen, which was assessed by determining the rate of significant toxicity. Secondary endpoints were the proportion of patients who achieved an overall response, a complete response, event-free survival at 12 months and 24 months from enrolment, progression-free survival, and overall survival; relapse of DLBCL; and duration of response. We deemed patients as assessable for the primary endpoint in the phase 1 portion if they completed the first cycle as planned. In the feasibility portion, all patients who received at least one dose of everolimus were included. This trial is registered with ClinicalTrials.gov, number NCT01334502. Between March 21, 2012, and Sept 15, 2014, we enrolled 26 patients into the study. Two were ineligible, therefore results are presented for 24 eligible patients. Nine patients were enrolled into the phase 1 portion of the trial (three given everolimus on days 1-10, and six given everolimus on days 1-14) without any dose-limiting toxicities; therefore, everolimus 10 mg/day given on days 1-14 with R-CHOP-21 was tested in 15 additional patients for a total of 24. One (5%, 95% CI 0-24%) of 21 patients had a toxicity during the feasibility phase-a treatment delay of 12 days due to grade 3 hypokalaemia possibly related to everolimus. The median follow-up was 21·5 months (IQR 17-29). 23 (96%, 95% CI 79-100%) of 24 patients achieved an overall response, and all 23 (96%, 79-100%) also attained a complete metabolic response by PET. The remaining patient withdrew consent after in cycle 1 and attained a complete response with R-CHOP alone. All 24 (100%) patients met 12-month event-free survival, and nine had sufficient follow-up data to be event-free at 24 months. None of the 24 patients had died by the last follow-up (March 30, 2016), and none had had a relapse with DLBCL. Because no events occurred during the study or follow-up, we were unable to assess the duration of response or progression-free survival. The most common grade 3-4 adverse events were haematological; the most common of these was grade 4 neutropenia in 18 (75%) of 24 patients. Five (21%) of 24 had grade 3 febrile neutropenia. The mTORC1 inhibitor everolimus given for 14 days in combination with R-CHOP-21 for patients with DLBCL is safe. These findings suggest that drugs that target the PI3K-mTORC pathway add benefit when combined with standard R-CHOP. The everolimus with R-CHOP regimen should be tested against standard R-CHOP alone in a randomised trial, to support the benefits of this novel combination noted in this study. National Cancer Institute of the US National Institutes of Health.

Predicting Low Accrual in the National Cancer Institute's Cooperative Group Clinical Trials.

The extent to which trial-level factors differentially influence accrual to trials has not been comprehensively studied. Our objective was to evaluate the empirical relationship and predictive properties of putative risk factors for low accrual in the National Cancer Institute's (NCI's) Cooperative Group Program, now the National Clinical Trials Network (NCTN). Data from 787 phase II/III adult NCTN-sponsored trials launched between 2000 and 2011 were used to develop a logistic regression model to predict low accrual, defined as trials that closed with or were accruing at less than 50% of target; 46 trials opened between 2012 and 2013 were used for prospective validation. Candidate predictors were identified from a literature review and expert interviews; final predictors were selected using stepwise regression. Model performance was evaluated by calibration and discrimination via the area under the curve (AUC). All statistical tests were two-sided. Eighteen percent (n = 145) of NCTN-sponsored trials closed with low accrual or were accruing at less than 50% of target three years or more after initiation. A multivariable model of twelve trial-level risk factors had good calibration and discrimination for predicting trials with low accrual (AUC in trials launched 2000-2011 = 0.739, 95% confidence interval [CI] = 0.696 to 0.783]; 2012-2013: AUC = 0.732, 95% CI = 0.547 to 0.917). Results were robust to different definitions of low accrual and predictor selection strategies. We identified multiple characteristics of NCTN-sponsored trials associated with low accrual, several of which have not been previously empirically described, and developed a prediction model that can provide a useful estimate of accrual risk based on these factors. Future work should assess the role of such prediction tools in trial design and prioritization decisions.

Adult cancer clinical trials that fail to complete: an epidemic?

The number and diversity of cancer therapeutics in the pipeline has increased over the past decade due to an enhanced understanding of cancer biology and the identification of novel therapeutic targets. At the same time, the cost of bringing new drugs to market and the regulatory burdens associated with clinical drug development have progressively increased. The finite number of eligible patients and limited financial resources available to evaluate promising new therapeutics represent rate-limiting factors in the effort to translate preclinical discoveries into the next generation of standard therapeutic approaches. Optimal use of resources requires understanding and ultimately addressing inefficiencies in the cancer clinical trials system. Prior analyses have demonstrated that a large proportion of trials initiated by the National Cancer Institute (NCI) Cooperative Group system are never completed. While NCI Cooperative Group trials are important, they represent only a small proportion of all cancer clinical trials performed. Herein, we explore the problem of cancer clinical trials that fail to complete within the broader cancer clinical trials enterprise. Among 7776 phase II-III adult cancer clinical trials initiated between 2005-2011, we found a seven-year cumulative incidence of failure to complete of approximately 20% (95% confidence interval = 18% to 22%). Nearly 48000 patients were enrolled in trials that failed to complete. These trials likely contribute little to the scientific knowledge base, divert resources and patients from answering other critical questions, and represent a barrier to progress.

How important are willingness to participate studies in encouraging patient enrollment in oncology trials?

Despite the 3.5% increase in the FY2014 National Institutes of Health budget compared with the previous cycle [1], the recent budget sequestration and increasing funding uncertainty for clinical trials underscores the importance of optimizing the design of cancer clinical trials to ensure successful completion, including a priori evaluation of strategies to maximize patient accrual. Currently, only half of National Cancer Institute (NCI) Cooperative Group trials are completed. Several factors contribute to the limited success rate of these trials, including poor study designs, insufficient funding, and regulatory hurdles. Despite a first-rate US health care system that has the greatest number of available oncology clinical trials, it is disappointing that only 3–5% of adults enroll in clinical trials [2]. The potential for both selective enrollment and underenrollment is increasingly cited by scientific review committees in questioning the feasibility of proposed trials, which is not surprising since cancer clinical trials are becoming increasingly complex, often combining multiple treatment modalities, employing targeted therapies, and having more radiology and biologic correlative studies. Nearly a decade ago, Halpern proposed prospective preference assessment (PPA) as a method to improve patient enrollment and identify subgroups of patients who may benefit from a potential trial [3]. With PPA, potential subjects are interviewed using five key components: presentation of a hypothetical trial resembling the planned trial, assessment of the patient’s understanding of the study design, open-ended questioning to assess motivations for and concerned about the planned trial, written questionnaires to evaluate patient’s stated willingness to participate in the planned trial, and assessment of their willingness to participate when one or more identified important factors is varied [3]. We recently used PPA to conduct the first series of studies of patients’ willingness to participate in radiation oncology trials. In 2011, our group performed a PPA of patients’ willingness to participate in a randomized control trial of proton beam therapy versus intensity-modulated radiotherapy for localized prostate cancer. We undertook this study because of the high cost of the two proposed treatment arms, as well as the potential for strong patient preferences for one treatment versus the other, both of which contributed to our uncertainty regarding the feasibility of the proposed trial. In our study, we prospectively enrolled and interviewed 46 patients using purposeful sampling to ensure a diverse sample based on travel distance, age, race and physician provider. Using semi-structured interviews, we presented patients with a hypothetical trial description and asked several open-ended and focused follow-up questions regarding both their motivations for and concerns about trial enrollment. Using qualitative research analytic techniques, we identified over 20 factors that impacted patients’ willingness to participate in the proposed randomized How important are willingness to participate studies in encouraging patient enrollment in oncology trials?

Gene expression profile analysis of human intervertebral disc degeneration.

In this study, we used microarray analysis to investigate the biogenesis and progression of intervertebral disc degeneration. The gene expression profiles of 37 disc tissue samples obtained from patients with herniated discs and degenerative disc disease collected by the National Cancer Institute Cooperative Tissue Network were analyzed. Differentially expressed genes between more and less degenerated discs were identified by significant analysis of microarray. A total of 555 genes were significantly overexpressed in more degenerated discs with a false discovery rate of < 3%. Functional annotation showed that these genes were significantly associated with membrane-bound vesicles, calcium ion binding and extracellular matrix. Protein-protein interaction analysis showed that these genes, including previously reported genes such as fibronectin, COL2A1 and β-catenin, may play key roles in disc degeneration. Unsupervised clustering indicated that the widely used morphology-based Thompson grading system was only marginally associated with the molecular classification of intervertebral disc degeneration. These findings indicate that detailed, systematic gene analysis may be a useful way of studying the biology of intervertebral disc degeneration.

Evaluation of Lymphangiogenic Factors, Vascular Endothelial Growth Factor D and E-Cadherin in Distinguishing Inflammatory From Locally Advanced Breast Cancer

BackgroundInflammatory breast cancer (IBC) is an aggressive form of breast cancer that on presentation resembles locally advanced breast cancer (LABC). This study identified molecular features of IBC and LABC to investigate pathogenesis. Materials and MethodsThis study involved 100 IBC cases identified in a national IBC registry and 107 non-IBC LABC cases from the National Cancer Institute's Cooperative Breast Cancer Tissue Resource (CBCTR). Vascular endothelial growth factor D (VEGF-D) and E-cadherin levels and lymphatic vessel density (LVD) measured by podoplanin staining were examined by immunohistochemistry on paraffin-embedded tumor specimens. Intralymphatic tumor emboli (ILTE) were assessed in IBC and non-IBC tumors. IBC cases diagnosed by clinicians but not meeting the case definitions of the American Joint Committee on Cancer (AJCC) or the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI)(designated atypical IBC) were compared with AJCC- and/or SEER-defined cases (designated classic IBC). ResultsE-cadherin levels were significantly higher in classic IBC cases compared with non-IBC cases (P = .031), whereas compared with classic IBC, patients with non-IBC LABC had significantly higher LVD (P = .0017) and VEGF-D levels (P < .0001). ILTE was marginally greater in classic IBC than in non-IBC (P = .046). The profile of laboratory values in atypical IBC cases more closely resembled those fitting classic IBC than LABC. ConclusionE-cadherin levels, LVD, VEGF-D expression, and to a lesser extent, ILTE differed between classic IBC and non-IBC LABC. The similarity of laboratory results between atypical IBC and classic IBC vs. LABC suggests the need for broadening both the AJCC and SEER case definitions for this disease.

Tobacco Assessment in Actively Accruing National Cancer Institute Cooperative Group Program Clinical Trials

Substantial evidence suggests that tobacco use has adverse effects on cancer treatment outcomes; however, routine assessment of tobacco use has not been fully incorporated into standard clinical oncology practice. The purpose of this study was to evaluate tobacco use assessment in patients enrolled onto actively accruing cancer clinical trials. Protocols and forms for 155 actively accruing trials in the National Cancer Institute's (NCI's) Clinical Trials Cooperative Group Program were evaluated for tobacco use assessment at enrollment and follow-up by using a structured coding instrument. Of the 155 clinical trials reviewed, 45 (29%) assessed any form of tobacco use at enrollment, but only 34 (21.9%) assessed current cigarette use. Only seven trials (4.5%) assessed any form of tobacco use during follow-up. Secondhand smoke exposure was captured in 2.6% of trials at enrollment and 0.6% during follow-up. None of the trials assessed nicotine dependence or interest in quitting at any point during enrollment or treatment. Tobacco status assessment was higher in lung/head and neck trials as well as phase III trials, but there was no difference according to year of starting accrual or cooperative group. Most actively accruing cooperative group clinical trials do not assess tobacco use, and there is no observable trend in improvement over the past 8 years. Failure to incorporate standardized tobacco assessments into NCI-funded Cooperative Group Clinical Trials will limit the ability to provide evidence-based cessation support and will limit the ability to accurately understand the precise effect of tobacco use on cancer treatment outcomes.

The New National Cancer Institute National Clinical Trials Network

The National Cancer Institute (NCI) Cooperative Group Program has been reviewed by three published studies in the last 7 years evaluating the efficiency and effectiveness of this national oncology clinical trials system. The recommendations for improvement from these reports have prompted NCI to transform the Cooperative Group Program into a new NCI National Clinical Trials Network (NCTN) to improve the efficiency of large clinical trials and increase the speed of cancer translational research. The new NCTN offers community-based clinical investigators new opportunities to advance cancer research in their community setting but also presents challenges in promoting community-based research.

Abstract 698: Overexpression of the aryl hydrocarbon receptor correlates with high tumor grade in human breast invasive carcinomas

Abstract The aryl hydrocarbon receptor (AhR) is a ligand-activated basic helix-loop-helix transcription factor which binds environmental poly aromatic hydrocarbons (PAH) and mediates their carcinogenic effects. Recent reports, including data from our laboratory implicate AhR in breast cancer development and progression independent of the receptor occupancy by PAH. In this study we investigated the potential of AhR as a stage specific marker of breast cancer. We examined the expression of AhR by immunohistochemistry in tissue microarrays (TMA) containing 192 specimens of clinically defined three stages of invasive breast cancer: node-negative (NN), node-positive (NP) and metastatic (Met) carcinoma. The TMA were obtained from the National Cancer Institute Cooperative Breast Cancer Tissue Resource [NCI-CBCTR] and were stained for AhR using high affinity antibody. The AhR staining was then scored by three evaluators, including two pathologists who were blinded to the study. Statistical analysis showed a significant correlation between the AhR expression and the carcinoma case type (NN, NP or Met) (p-value of ANOVA is &amp;lt; 0.0003), and although there is a significant difference of AhR expression among carcinoma case type of white women (p&amp;lt; 0.0017) there is no significant difference for black women (p&amp;lt;0.0968). There is also a strong positive correlation between the receptor expression and the tumor grade (p &amp;lt;0.0001). While there is no correlation with the status of estrogen or progesterone receptors (p= 0.1643 and 0.1884, respectively), there is strong correlation of high AhR expression and invasive breast carcinoma in women over 50 years old (p&amp;lt;0.0043). In conclusion, our findings identify the AhR as a new predictive clinical marker for metastatic breast cancer and a unique target for the design of novel selective inhibitors for therapeutic intervention of metastatic breast cancer. More importantly, the AhR overexpression identifies a subset of patients who could benefit from therapy targeting this receptor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 698. doi:1538-7445.AM2012-698

Published methodological quality of randomized controlled trials does not reflect the actual quality assessed in protocols

ObjectivesTo assess whether the reported methodological quality of randomized controlled trials (RCTs) reflects the actual methodological quality and to evaluate the association of effect size (ES) and sample size with methodological quality. Study Design and SettingSystematic review. This is a retrospective analysis of all consecutive phase III RCTs published by eight National Cancer Institute Cooperative Groups up to 2006. Data were extracted from protocols (actual quality) and publications (reported quality) for each study. ResultsFour hundred twenty-nine RCTs met the inclusion criteria. Overall reporting of methodological quality was poor and did not reflect the actual high methodological quality of RCTs. The results showed no association between sample size and actual methodological quality of a trial. Poor reporting of allocation concealment and blinding exaggerated the ES by 6% (ratio of hazard ratio [RHR]: 0.94; 95% confidence interval [CI]: 0.88, 0.99) and 24% (RHR: 1.24; 95% CI: 1.05, 1.43), respectively. However, actual quality assessment showed no association between ES and methodological quality. ConclusionThe largest study to date shows that poor quality of reporting does not reflect the actual high methodological quality. Assessment of the impact of quality on the ES based on reported quality can produce misleading results.

Clinical Cancer Advances 2011: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology

A message from ASCO'S President. It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the "War on Cancer." The bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real-time information that can inform the care of every patient with cancer as well as connect patients with their entire medical teams. The rapid learning system will form a continuous cycle of learning: securely capturing data from every patient at the point of care, drawing on evidence-based guidelines, and evaluating quality of care against those standards and the outcomes of other patients. Clinical trials are another area in which collaboration is critical. Increasing clinical trial participation will require commitment across the cancer community from physicians, patients, insurers, hospitals, and industry. A 2010 report by the Institute of Medicine described challenges to participation in trials by both physicians and patients and provided recommendations for revitalizing clinical trials conducted through the National Cancer Institute's Cooperative Group Program. ASCO has pledged its support for the full implementation of these recommendations. More broadly, ASCO recently outlined a bold vision for translational and clinical cancer research for the next decade and made recommendations to achieve that vision. Accelerating Progress Against Cancer: ASCO's Blueprint for Transforming Clinical and Translational Research, released in November, calls for a research system that takes full advantage of today's scientific and technologic opportunities and sets a high-level agenda for policy makers, regulators, and advocates. Cancer research has transformed cancer care in the past forty years, and this year's Clinical Cancer Advances illustrates how far we have come in the past year alone. We now have a tremendous opportunity to use today's knowledge and collaborate across all facets of cancer care to conquer this deadly disease. Michael P. Link, MD President American Society of Clinical Oncology.

The 2010 National Comprehensive Cancer Network (NCCN) research benchmarking survey (RBS): Clinical trials in the academic cancer center.

6116 Background: The 2010 NCCN RBS focused on therapeutic clinical trial volume, accrual rates, and protocol review processes at NCCN centers. The primary aim was to benchmark clinical trials activity including trial sponsorship, patient accrual, and the steps involved in protocol review. Methods: The survey collected quantitative and descriptive data on therapeutic trials, accruals, and sponsors. In addition, because the steps required for activation of clinical trials may result in delays and increase costs, the 2010 RBS focused on the processes and timeframes involved in protocol review. Results: Of newly reportable patients (105,917) from 19 centers reporting accruals over a 12-month period, 16,018 (15.1%) were recruited to therapeutic clinical trials; 6,097 trials (all phases) were reported. The average number of accruals per trial (all sponsors) was 2.63. 39% of trials (2,367) were sponsored by National Cancer Institute Cooperative Groups (NCI CGs), with 19% (2,866) of patient accruals attributed to NCI CG trials (1.21 accruals/trial). Comparatively, 22% of trials (1,364) were institutionally sponsored, while 40% of accruals (6,087) were enrolled in these trials (4.46 accruals/trial). 30% of trials (1,827) were industry sponsored (1,827), and accounted for 27% of accruals (4,016), or 2.20 per trial. Other peer-reviewed mechanisms accounted for the balance of trials and accruals. A broad range of timelines were reported for the steps involved in protocol review and activation indicating that 1) there are likely best practices that merit investigation and 2) further refinement and standardization of timeline definitions are warranted. An analysis of protocol review timelines is underway. Conclusions: Clinical research constitutes a core mission of NCCN centers. NCCN benchmarking efforts are undertaken to improve clinical trials operations and ultimately to impact the delivery of new therapies to patients. Accruals per trial for all sponsors appear low; the rate of 1.21 accruals per NCI CG trial is of particular concern. Further development of benchmarks and best practices will promote enhanced operations, timely review processes, and increased patient accrual.

Conducting Cancer Control and Survivorship Research via Cooperative Groups: A Report from the American Society of Preventive Oncology

As the number of cancer survivors expands, the need for cancer control and survivorship research becomes increasingly important. The National Cancer Institute (NCI) Cooperative Groups may offer a viable platform to perform such research. Observational, preventive, and behavioral research can often be performed within the cooperative group setting, especially if resources needed for evaluation are fairly simple, if protocols are easily implemented within the typical clinical setting, and if interventions are well standardized. Some protocols are better suited to cooperative groups than are others, and there are advantages and disadvantages to conducting survivorship research within the cooperative group setting. Behavioral researchers currently involved in cooperative groups, as well as program staff within the NCI, can serve as sources of information for those wishing to pursue symptom management and survivorship studies within the clinical trial setting. The structure of the cooperative groups is currently changing, but going forward, survivorship is bound to be a topic of interest and one that perhaps may be more easily addressed using the proposed more centralized structure.

Clinical Cancer Advances 2010: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology

A MESSAGE FROM ASCO'S PRESIDENT Like many health professionals who care for people with cancer, I entered the field because of specific patients who touched my heart. They still do. In an effort to weave together my personal view of what the American Society of Clinical Oncology (ASCO) stands for and the purpose the organization serves, my presidential theme this year is “Patients. Pathways. Progress.” Patients come first. Caring for patients is the most important, rewarding aspect of being an oncology professional. At its best, the relationship between doctor and patient is compassionate and honest—and a relationship of mutual respect. Many professional organizations have an interest in cancer, but no other society is so focused on the entire spectrum of cancer care, education, and research. Nor is any other society as particularly interested in bringing new treatments to our patients through clinical trials as ASCO is. Clinical trials are the crux for improving treatments for people with cancer and are critical for continued progress against the disease. “Pathways” has several meanings. Some pathways are molecular—like the cancer cell's machinery of destruction, which we have only begun to understand in recent years. But there are other equally important pathways, including the pathways new therapies follow as they move from bench to bedside and the pathways patients follow during the course of their diseases. Improved understanding of these pathways will lead to new approaches in cancer care, allowing doctors to provide targeted therapies that deliver improved, personalized treatment. The best pathway for patients to gain access to new therapies is through clinical trials. Trials conducted by the National Cancer Institute's Cooperative Group Program, a nationwide network of cancer centers and physicians, represent the United States' most important pathway for accelerating progress against cancer. This year, the Institute of Medicine released a report on major challenges facing the Cooperative Group Program. Chief among them is the fact that funding for the program has been nearly flat since 2002. ASCO has called for a doubling of funding for cooperative group research within five years and supports the full implementation of the Institute of Medicine recommendations to revitalize the program. ASCO harnesses the expertise and resources of its 28,000 members to bring all of these pathways together for the greater good of patients. Progress against cancer is being made every day—measurable both in our improved understanding of the disease and in our ability to treat it. A report issued in December 2009 by the National Cancer Institute, the Centers for Disease Control and Prevention, the American Cancer Society, and the North American Association of Central Cancer Registries found that rates of new diagnoses and rates of death resulting from all cancers combined have declined significantly in recent years for men and women overall and for most racial and ethnic populations in the United States. The pace of progress can be and needs to be hastened. Much remains to be done. Sustained national investment in cancer research is needed to bring better, more effective, less toxic treatments to people living with cancer. Pathways to progress continue in the clinic as doctors strive to find the right treatments for the right patients, to understand what represents the right treatments, and to partner with patients and caregivers for access to those treatments. This report demonstrates that significant progress is being made on the front lines of clinical cancer research. But although our nation's investment in this research is paying off, we must never forget the magnitude of what lies ahead. Cancer remains the number two killer of Americans. Future progress depends on continued commitment, from both ASCO and the larger medical community. George W. Sledge Jr, MD President American Society of Clinical Oncology

Accrual experience of National Cancer Institute Cooperative Group phase III trials activated from 2000 to 2007.

Recent reports have suggested that 40% or more of National Cancer Institute (NCI) -sponsored Cooperative Group phase III trials failed to achieve their accrual goals. We examine in detail the accrual experience of the Cooperative Group phase III trials. All Cooperative Group phase III trials activated from 2000 to 2007 were examined for their accrual experience. For trials that stopped accrual with < 90% of their accrual goal, the reasons for having < 90% accrual were documented. We focus on trials that ended with < 90% accrual because of inadequate accrual rates rather than for other reasons, such as an interim monitoring analysis by an independent data monitoring committee that stops the trial early because one treatment is clearly superior. There were 191 trials activated from 2000 to 2007. We project that 22.0% of these trials will have < 90% accrual because of inadequate accrual rates. We project that there will be 176,627 patients eventually accrued on the 191 trials (current accrual, 154,579) and that 2,991 of these patients will be on trials that have < 90% accrual because of inadequate accrual rates (1.7%). For nonpediatric cancer trials, the corresponding percentages are 26.7% and 2.0%. We find that insufficient accrual rates are not as high as previously reported and that only a small proportion of patients were enrolled on trials that ended with insufficient accrual because of an inadequate accrual rate. NCI has implemented new procedures to reduce the number of trials that fail to reach their accrual goals and to minimize the number of patients accrued on these trials.