MAGNETIC RESONANCE SPECTROSCOPY AND CANCER TREATMENT NIH GUIDE, Volume 21, Number 20, May 29, 1992 PA NUMBER: PA-92-86 P.T. 34 Keywords: Cancer/Carcinogenesis Medical/Diagnostic Imaging National Cancer Institute PURPOSE The National Cancer Institute (NCI), through the Diagnostic Imaging Research Branch (DIRB) of the Radiation Research Program, seeks grant applications through Interactive Research Project Grants (IRPGs) in order to establish multidisciplinary research in the area of early detection and prediction of tumor response to treatment using magnetic resonance imaging (MRI)-guided magnetic resonance spectroscopy (MRS). HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This program announcement, Magnetic Resonance Spectroscopy and Cancer Treatment, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017- 001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit, public and private organizations, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT It is intended that this program will be supported through the interactive R01 mechanism. Elements of the program may be supported as individual R01 grants. The NCI seeks to encourage the coordinated submission of related research project grant applications from investigators who want to collaborate on a common cancer research theme, but do not require extensive shared physical resources or core functions. A minimum of three independent investigators with related research objectives are encouraged to submit concurrent, collaborative, cross-referenced individual research project grant applications (R01) that share a common research focus. Applications may be from either a single institution or a consortium of institutions. Applications will be reviewed independently for scientific merit. Meritorious applications will be considered for funding both as independent awards and in the context of the overall proposed collaboration. Applicants will be responsible for the planning, direction, and execution of the proposed projects. One Principal Investigator out of the group MUST be identified as the "Program Coordinator," and must be cited in all applications on page 2 of form PHS 398. Individual investigators may request funds for the time and effort contributed toward the coordination of the overall research and for collaborative resource activities. Additional information about the interactive R01 mechanism may be found in the NIH Guide for Grants and Contracts, January 10, 1992, in PA-92-29, "Interactive Research Project Grants for Cancer." Awards will be administered in accordance with Public Health Service Policy as described in the PHS Grant Policy Statement, DHHS. Publication No. (OASH) 90-50,000 revised October 1, 1990. RESEARCH OBJECTIVES Background Information Conventional, or proton, MRI provides predominantly anatomic information, whereas MRS is essentially an in vivo assay of tissue biochemistry. Recently, it has become possible to integrate MRS with routine MRI, so that local abnormalities detected by MRI can be examined biochemically by MRS before and after therapeutic interventions. In contrast to currently available imaging methodologies, which rely predominantly on changes in tumor size to evaluate therapeutic response, MRS can detect early biochemical changes in tumor composition that precede morphologic changes in response to therapeutic interventions. Studies in animal tumors have provided strong evidence that MRS can readily observe the effects of therapies on tumor metabolism. However, it is not entirely clear if MRS could be used in humans for prediction of therapeutic outcome or as a guide for treatment planning. At present, few clinical studies have been done in this area. More work is required to determine if the changes seen in animal tumor models are evident in their human counterparts and, if so, to investigate the underlying biologic mechanisms. The focus of the proposed research is to examine proton MRI-guided localized MRS as a tool for early detection and prediction of tumor response to treatment. The clinical application of MRS in oncology is in its early stages of development. The majority of clinical MRS studies to date have been performed in a limited number of patients. In spite of the technical limitations imposed on early clinical studies, the preliminary phosphorus-31 MRS results indicate that changes in pH, PME. and PDE levels may be predictive of response to radiation and chemotherapy. Moreover, preliminary proton MRS studies in humans indicate the differences in the levels of choline, N-acetyl aspartate, and, in some instances, lactate or alanine both between tumor and normal brain and within tumors. The developments of the MRS methodology and technology have progressed considerably in the areas of spatial localization, spectral editing, data analysis, quantitation, and data presentation. At a recent NCI workshop, an expert panel identified the need for carefully planned clinical studies. The goal of this initiative is to conduct well-focused, prospective clinical studies using currently available, routinely applicable, methodology to begin comprehensive testing of the potential for 31P MRS to predict and/or detect therapeutic response in patients with tumors. Given the limited resources available at any one institution and the effort required to perform repeated measurements in each patient for response predictor studies, it seems prudent to coordinate such studies among several institutions. The critical issue in these studies is quality control, i.e., setting precise standards for performance and interpretation of spectroscopic studies. Research Goals and Scope This new program announcement will stimulate the scientific community to research, in a centrally coordinated fashion, the utility of MRI-guided MRS for early detection and prediction of therapeutic response in patients with tumors. A consensus-based development of the experimental design will include data acquisition, presentation and processing (e.g., standards of MRS performance, well-defined technical requirements, and method(s) of spectral localization, quantification, and data analysis). This announcement seeks to encourage the following research topics in proton MRI-guided MRS in preclinical and clinical cancer research: o Detection and prediction of immediate treatment response o Prediction of final outcome o Evaluation of the direct effect of drugs o Differentiation of viable tumor from treatment-induced necrosis, edema, and scar It is also expected that the proposed studies will address the following needs: o In vivo metabolic characterization of human tumors o Correlation of metabolic characteristics with histological features (e.g., tissue types, tumor grade) o Correlation of metabolic characteristics with clinical and biological behavior (growth rate, degree of differentiation, probability of recurrence, metastatic potential) STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in the Research Plan, 1-4, AND summarized in 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for this program announcement. These forms are available at most institutional business offices, the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892, telephone (301) 496-7441, and the NCI program director named below. The PA number and title must be typed on line 2a of the face page of the application form. The use of the IRPG mechanism must be mentioned briefly in form PHS 398, Sections 1-4 of the Research Plan. The goal of the collaborative efforts MUST be identified in the specific aims of each application, with the major rationale and explanation for the use of the IRPG mechanism to be given in Section 7, Consultants/Collaborators. A complete list of applications in the IRPG must be provided in Section 7, as well as an indication of the specific collaborations to be established for the individual application under consideration. Requests for limited shared resources, if any, must be proportionally budgeted in each application based on anticipated use, with a full explanation given in the budget. Personnel Time and Effort requests for management of shared resources are allowable. If consortium arrangements between independent institutions are proposed that would make transfer of funds for required new equipment impractical, the entire equipment request may be budgeted by the responsible laboratory. This must be clearly justified. All PHS and NIH grants policies will apply to applications received in response to this announcement. If the applicant has an approved assurance covering the research (multiple project assurance for human subjects/full assurance of compliance for animal subjects), the applicant should provide with the application certification of institutional review board (IRB) approval, if humans are involved, and verification of the institutional animal care and use committee (IACUC) approval, if animals are involved. These reviews and approvals should occur PRIOR TO SUBMISSION of the applications for award and the certifications and verifications should be SUBMITTED WITH the applications. Failure to provide required certifications and verifications within applications could result in deferral or rejection of the application. If animals or humans will be subjects of research at PERFORMANCE SITES OTHER THAN THE APPLICANT ORGANIZATION, the applicants must identify, with the application, the assurance status of each participant. Failure to provide this information within applications may result in deferral or rejection. Submit a signed, typewritten original of the application, including the Checklist, and five signed, exact photocopies, in one package to the address below. The photocopies must be clear and single sided. Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Upon receipt, applications will be reviewed by the Division of Research Grants (DRG) for completeness. Incomplete applications will be returned to the applicant without further consideration. Those applications judged to be complete will be further evaluated for scientific and technical merit by study sections of the DRG. Following the scientific and technical review, the applications will receive a second level of review by NIH staff who consider the application in light of the special needs of the Institute. REVIEW PROCEDURES Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the customary NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program balance among research areas of the announcement INQUIRIES Written and telephone inquires concerning the objectives and scope of this program announcement and inquiries about whether or not specific proposed research would be responsive are encouraged and should be directed to: Faina Shtern, M.D. Chief, Diagnostic Imaging Research Branch Radiation Research Program National Cancer Institute Executive Plaza North, Suite 800 Bethesda, MD 20892 Telephone: (301) 496-9531 Dr. Shtern welcomes the opportunity to clarify any issues or questions from potential applicants. Direct inquiries regarding budgetary/administrative issues to: Joan Metcalfe Grants Management Specialist Grants Administrative Branch National Cancer Institute Executive Plaza South, Room 242 Bethesda, MD 20892 Telephone: (301) 496-7800, extension 28 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395, Cancer Treatment Research. Awards are made under the authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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