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Lung Cancer Integration and Implementation (I2) Team
Business Plan: Executive Summary Phase I

A.   Introduction and Vision

In 2004, an estimated 173,770 Americans were diagnosed with lung cancer, and there were an estimated 160,440 deaths, representing 13 percent of all incident cancers annually and 28 percent of all cancer deaths. Lung cancer remains the leading cause of cancer mortality for both men and women in the United States, killing more patients than the next five most common cancers combined. These sobering statistics are compounded by the inescapable fact that there have been only the most modest of improvements in five year survival rates. The Lung PRG report noted that progress will continue to be limited in the future by the absence of a well-defined mechanism and infrastructure to enroll patients in trials and systematically collect and archive tissue. Progress has also been limited in applying new therapeutic approaches for patients with stage I and II lung cancer, in verifying the clinical utility of molecular predictors of prognosis or response to treatment, and in being able to rapidly and efficiently perform phase I and II studies of new targeted therapies with defined biologic endpoints. It is thus clear that we must take drastic and bold actions if we are to positively impact these statistics.

In order to accomplish this Vision we have targeted three critical strategies:

In order to implement these critical strategies, we are also proposing that lung cancer be a major focus of activity for:

Our implementation plan has been crafted as a comprehensive approach that does not duplicate existing or planned initiatives. Rather we will build upon those initiatives with a lung-specific focus and for those initiatives without such a focus, we request redirection of efforts to include a lung cancer focus. We are not suggesting that all existing activities related to lung cancer pre-clinical and clinical research be included in the scope of the I2 Lung Team. Instead, we strongly suggest that the Team focus on high opportunity and potentially high return strategies. We believe that the efforts of the Team should not be diverted by the incorporation of incremental strategies but should instead focus on transformational strategies.

Finally, we recognize the unique opportunity for the Lung Cancer Integration and Implementation Team to develop strategic alliances with the two parallel Integration and Implementation teams focused on Imaging and Bioinformatics.

This proposal is for Phase 1 activities (Year 1) of a multi-year business plan to achieve the 2015 Vision. The proposed activities are foundational and are included in initial phase activities for the proposed Product Lines whatever the details derived for out years.

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B.   Management and Organizational Structure

There is no single operational focus within NCI dedicated for lung cancer initiatives in prevention, diagnosis and therapy. We therefore propose to establish a "Virtual Distributed Corporate" model (I2 Lung Cancer) to manage the business plan. In order to operationalize this business model, we also propose to create the position of Program Director for I2 Lung Cancer. The activities necessary to accomplish the proposed outcome(s) will be implemented and accomplished through NCI Divisions, Programs, and Branches chosen as "best of breed" with proven and documented areas of expertise, and accomplished using a variety of funding mechanisms.

We also propose the immediate creation of a Lung Cancer Scientific Advisory Committee (LCSAC) to serve as an advisory body to provide scientifically grounded advice to the NCI Director (through the Program Director of I2 Lung Cancer) on the status of cross-cutting lung cancer research activities across research entities. The committee, with broad intra- and extramural representation, will be appointed by the Director of the NCI, and will meet in person at least twice a year initially and by monthly teleconferencing. Their mandate will be to prioritize key strategies and to provide strategic direction and oversight to the Director on all lung cancer issues, to monitor progress over time, and to identify critical questions and unmet needs across the spectrum of lung cancer research.

The Program Director and the LCSAC will have the responsibility of completing the business plan during the first year of activity, following an initial State of the Science meeting. This business plan will include annual budgetary projections as well as intermediate benchmarks by which the Senior Management and the Institute can measure progress towards the 2015 Vision and the long term deliverables for each of the Product Lines as well as for I2 Lung Cancer as an integrated entity.

In order to achieve synergy with the Clinical Trials Working Group (CTWG) recommendations, our proposal also includes creating a Lung Cancer Scientific Steering Subcommittee constituted as a subcommittee of the proposed LCSAC to provide advice to the NCI director on the conduct, oversight, and implementation of lung cancer clinical trials across the Institute, to involve the broad oncology community, facilitate open communication and increase the involvement of patients and community oncologists in clinical trials.

We also recommend an augmentation of the current CISNET to become "CISNET+ "to derive applicable metrics by which the I2 Lung Team will measure its impact on both patient and societal levels.

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C.   Product Lines

1.   Tobacco Control

Significantly higher all cause and lung cancer death rates have been noted in continuing smokers compared with intermittent and sustained quitters. These findings support the important contribution of smoking cessation to reducing lung cancer mortality. However, fewer than 40% of providers currently recommend specific treatment for tobacco use. Furthermore, even with combined behavioral and pharmacologic interventions, quit rates are no more than 15-25%. Therefore, we outline a multi-pronged, transdisciplinary, 3D approach to improve the success rates of smoking cessation and prevention.

Although primary prevention of initiation will not have an impact on the 2015 I2 Lung Vision, we propose to include support for the prevention of tobacco use, although the timing of investment in prevention is somewhat delayed in our business plan and the amount initially invested will be lower than that proposed for cessation efforts.

1.2   Development:
To coordinate the research enterprise on tobacco control by developing a web-based network environment for sharing clinical trial, surveillance, laboratory, and related data on tobacco to link with caBIG and the DCCPS ISIS initiatives. The objectives are to move the treatment of tobacco dependence more rapidly from the clinic to practice, to create greater linkage through interactive workgroups between biomedical and behavioral data, and to provide rapid updates to the scientific community. This initiative could serve as an exemplar for other behavioral databases and collaborations.

1.3   Delivery:
To create a coalition of organized medicine (including pediatric and adult health care providers), pharma, and advocacy groups in order to maximize awareness and use of updated Clinical Guidelines for Smoking Cessation from The Agency for Healthcare Research and Quality (AHRQ), and to widely disseminate up-to-date information about the most effective smoking cessation tools, and especially the toll free quitline. The aims are to maximize the number of smokers who quit, promote productive public-private partnerships, and by developing mass media interventions of an extended duration, increase consumer demand for effective behavioral and pharmacologic treatments.

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2.   Early Detection

The current overall 5 year lung cancer survival rates for men are 13.6% compared with 17.2% for women. Since over half of all lung cancers are diagnosed at late stages, for which 5 year survival rates are only 3%, we highlight the need for effective and validated early detection techniques. We also plan to build upon the lung specific projects of I2 Imaging, upon which we propose critical opportunities to leverage several lung cancer-specific objectives to realize these objectives at substantial cost savings.

2.1   Allocate resources for the maintenance and oversight of the ACRIN-NLST Specimen Biorepository both during and after the period of the trial to oversee the quality and integrity of samples, development of seamless integration of biospecimens with all associated metadata, and ensure the optimal uses of these depletable archives for the most promising molecular research. Also, fund advertising of the repository to the scientific community.

2.2   Fund collection of remnant tissue specimens from participants with proven lung cancers, and incorporate biospecimen and imaging data within the Image Archive being established.

2.3   Fund collection of pathology tissue from lung cancer cases diagnosed in the PLCO Trial.

2.4   Promote standardized application of proteomic technologies across platforms and sites through a proteomics initiative. Such an initiative could potentially be part of the proposed NCI-wide Molecular Biomarkers Initiative, once approved.

2.5   Bootstrap on existing initiatives that promote the development and validation of in vivo imaging in early lung cancer detection. These programs include:

  1. addition of quantitative image analysis within the Imaging Informatics infrastructure to house lung cancer-related image data with associated metadata, including image-specific data, annotations on image data in DICOM and non-DICOM presentation states, clinical data, and all biospecimen and associated data.
  2. building upon the infrastructure for validated software platforms provided by the NCI-sponsored Lung Imaging Database Consortium (LIDC), a web-accessible resource for computer-aided diagnosis (CAD) methods for lung cancer detection and diagnosis and for "change recognition" software tools developed in RIDER, that likely will have importance within serial CT imaging screening strategies as well.

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3.   New Drug Development and Imaging of Response to Therapy

Targeted drug development is impeded because only a fraction of the molecular targets involved in lung tumorigenesis has been identified in small numbers of subjects. With large-scale sequencing now a viable tool for discovery, a unique opportunity exists to create a well-defined strategy to systematically identify all the genomic and epigenomic lesions associated with lung cancer. These genetic insights and advances in biology will drive new drug development and help in monitoring of therapy response. Success requires coordinated efforts to improve target identification, and the development of functional imaging agents, and novel clinical trial methodologies.

3.1   Synergize with the Human Cancer Genome Project Initiative proposed by the NCAB Working Group chaired by Drs. Lander and Hartwell, by launching parallel lung-specific projects as proof of principle studies to identify all the genomic and epigenomic lesions associated with lung cancer. Such a systematic characterization of lung cancer could transform treatment, by improving selection of therapeutic targets with higher efficacy and decreased side effects; identification of patients most likely to respond, rational development of combination therapies; resolution of cancer into homogeneous groups; improved understanding of the molecular events triggered by carcinogenic exposures, and refined estimates of susceptibility. We strongly urge that lung cancer be the #1 priority for the Human Cancer Genome Project with immediate funding to accomplish the recommendations.

3.2   Define the contribution of inflammation, infection, and injury to lung carcinogenesis, with the aim of identifying appropriate targets for cancer treatment and prevention. It is recognized that the microenvironment may also be an important factor in developing therapeutic approaches.

3.3   Speed the translation of these findings to clinical care. We propose an alternative drug delivery system initiative for lung cancer treatment or prevention, synergizing with the Nanotechnology initiative. The goal is to promote delivery of multiple payloads for combination therapy, and use of reporting systems to target receptors and avoid systemic toxicities, potentially allowing use of agents at concentrations previously unattainable.

3.4   To advance the science of imaging response assessment with molecular imaging technologies that directly reflect response to targeted therapies and by providing uniform, high quality imaging acquisition, quality control, and analysis within the conduct of clinical trials. A multi-pronged approach is proposed:

  1. Support the creation and operation of Lung Imaging Response Assessment Team/s (L-IRATs) to establish common operating standards for image acquisition protocols, quantitative image analyses, semi-structured reporting methods, and participating in the specification of image acquisition parameters / protocols for Phase 2 and 3 clinical trials, providing quality control of images, and performing decentralized over-reads (including a consensus process for discrepancies). The actual structure/function/organization/funding of this lung IRAT proposal remains to be determined after further input is obtained from stakeholders.
  2. Establish a "Lung Cancer Meta-directory" to link lung cancer-related image data with associated metadata, including imaging, genomic, transcriptional, proteomic, metabolomic, and clinical manifestations of lung cancer. This "roadmap" activity is a collaboration among I2 Lung Cancer, I2 Imaging, and I2 Informatics and is to be operationalized through caBIG workspaces.
  3. Formulate accepted standards for dynamic contrast-enhanced imaging with MR and CT with the potential to register the functional consequences of anti-angiogenesis therapy, thereby providing early evidence of treatment efficacy.
  4. Support the ongoing efforts of the Image Guided Intervention (IGI) Product Line within I2 Imaging related to the minimally invasive therapy of early stage lung cancer and eventually of screen detected lesions (pre-cancer, early cancer, and lesions not characterized in high risk individuals).

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