Cancer clinical trials provide the evidence on which sound oncology practice is based. Assuring rapid enrollment to clinical trials is a major goal of all sponsors and funders and depends to a great extent on the efficiency of the infrastructure that supports this research. Increasingly, National Cancer Institute- and biopharmaceutical-sponsored trials encourage the participation of physicians engaged in community practice, in addition to the more traditional involvement of academic institutions. The characteristics that ensure quality research in these varied practice settings are reviewed in this chapter and tools that facilitate enrollment are described.

The traditional and accelerated titration (AT) designs are two frequently utilized Phase I clinical trial designs. Although each design has theoretical advantages and disadvantages, a summary of the practical application of these theories has not been reported. We report our center's experience in evaluating novel agents using both types of Phase I trial designs over a 13-year period. Results from nine Phase I clinical trials of multiple cytotoxic agents conducted at Wayne State University/Karmanos Cancer Institute in Detroit, MI, and published from 1995-2005 were analyzed for this report. Parameters analyzed included the number of patients, the number of dose levels, the total time to completion of the study, and adverse events. The mean number of patients treated on four Phase I trials using the traditional Phase I trial design was 34 compared to a mean of 23.8 patients treated on five Phase I trials using the AT schema. The mean number of dose levels in patients treated using the traditional Phase I trial design was 8.8 (range 7-11) compared to a mean of 10.6 (range 7-15) dose levels using the AT design. The mean length of study time (25-26 months) was similar in both trial designs. The theoretical advantages and disadvantages of both Phase I trial designs did not readily emerge in their actual application in clinical trials conducted at our institution.

The large number of negative phase III trials in oncology over the last several years has renewed interest in refining phase II oncology clinical trials to maximize the chances of success in phase III testing. More efficient phase II study designs will improve our ability to identify promising agents for testing while accurately identifying nonefficacious agents. Recognizing that new paradigms of phase II trial designs need to be developed, the Clinical Trial Design Task Force of the National Cancer Institute (NCI) Investigational Drug Steering Committee has tackled the question of improving efficiency of phase II clinical trials. In this issue of CCR Focus, four of the major topics discussed are presented. First, the task force recommended that alternate phase II end points should be studied. Second, depending on the characteristics of the specific trial and study population, historical controls or a randomized design may be more appropriate. Third, rational incorporation of biomarkers into phase II trials should be encouraged. Last, novel imaging modalities will be critical in evaluating the clinical benefit of new cytostatic agents.

In 2006, i.p. chemotherapy re-emerged as a controversial topic in debates about the optimal treatment for women with advanced epithelial ovarian cancer. In this paper, we address the rationale behind i.p. chemotherapy, the data supporting its use, the selection of appropriate patients for i.p. chemotherapy, how best to avoid and manage the toxicities observed with i.p. chemotherapy, and directions for future research.

On the basis of three large randomized phase III trials, the National Cancer Institute (NCI) issued a Clinical Announcement in January 2006 recommending that women with optimally debulked stage III ovarian cancer and their physicians consider a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy. The combination of IV and IP chemotherapy is associated with a clinically significant benefit in survival, although it does also confer an increased risk of toxicity compared to IV chemotherapy alone. The NCI Clinical Announcement was issued as part of a broader educational campaign, designed in conjunction with professional societies, cancer centers, Clinical Trials Cooperative Groups, and cancer advocacy organizations. The further development of IP chemotherapy in ovarian cancer requires additional clinical and translational research.

Intraperitoneal (IP) chemotherapy is a preferred treatment option that should be offered to all women for front-line treatment of stage III optimally debulked ovarian cancer. Patients should be provided with information on the survival and toxicity for both IP and intravenous (IV) therapies, as well as practical information about the administration of each regimen, so that they may play an active role in the decision-making process. When making a decision between IP and IV therapeutic options, the experience and preference of the oncologist are critical factors in determining appropriate therapy for each woman.

6632 NCI has developed a central IRB (PedCIRB) to review NCI-sponsored pediatric clinical trials conducted by the Children's Oncology Group (COG). COG comprises ∼200 U.S. medical institutions and protocol activation traditionally requires separate protocol review by each local IRB (LIRB) and, subsequently, a review of each protocol amendment and significant adverse event. The PedCIRB model seeks to increase patient protection by improving the expertise of protocol reviewers and making their review available to all PedCIRB participating institutions. The PedCIRB consists of experts in pediatric oncology, pediatric medicine, nursing, pharmacy, bioethics, biostatistics, as well as patient advocates and childhood cancer survivors. The PedCIRB model also eliminates redundant reviews, reduces administrative burdens on local COG investigators and LIRBs, and can accelerate the pace of local protocol activation, thus increasing the availability of clinical trials to children with cancer. The PedCIRB conducts a full board protocol review that is available via a confidential website to participating LIRBs. LIRBs can choose to perform a facilitated review, using PedCIRB materials, that focuses on local concerns, rather than a full LIRB protocol review. If the LIRB accepts the PedCIRB review, the PedCIRB becomes the IRB of record for that protocol and takes responsibility for the review of subsequent protocol amendments, adverse events and continuing reviews. Since starting in November 2004, the PedCIRB has reviewed 59 protocols. Initial reviews resulted in 44 approvals pending modification and 15 protocols being tabled for further information. The time from protocol submission to final approval by the PedCIRB has ranged from 3 to 28 weeks with an average time of 16.9 weeks during year one and 12.7 weeks during year two of the project. As of November 2006, 117 of a possible 197 U.S. COG institutions (59%) have signed on to the PedCIRB initiative and 70% of the participating institutions have conducted facilitated reviews (total 750) for the 30 protocols available on the PedCIRB website. The PedCIRB's influence on protocol development and patient accrual timelines will be discussed. No significant financial relationships to disclose.

Taxonomy and nomenclature of normal and abnormal states of consciousness have been highly variable, imprecise and sometimes confusing, because the terms used to describe them have been given different meanings depending on medical field (e.g.neurology and psychiatry) and language.Compounding the difficulty is the fact that the terms continue to be changed in an attempt to reflect pathophysiology of disturbed consciousness which, however, is still not fully understood.In this article the terminological development and various definitions of the terms sopor, stupor, delirium, akinetic mutism and coma vigile,"apallisches Syndrom" ("apallic syndrome") or vegetative state are being described with special emphasis on the German and English medical usage and some discrepant denotations.Acute confusional state ("akuter Verwirrtheitszustand") e.g. has been classified either as a symptom orinauspiciously -also as syndrome/disease thereby making it synonymous to delirium.The English usage of the term "stupor" in neurology instead of "sopor" (semi-comatose state) stands in contrast to the psychiatric usage, where stupor implies absence of voluntary movement and responsiveness to external stimuli while being fully awake (e.g.dissociative stupor).German designations such as Bonhoeffer's "akuter exogener Reaktionstyp" ("acute exogenous reaction type") as umbrella term for symptomatic psychoses, Wieck's "Durchgangssyndrome" ("transitional syndromes") for acute reversible organic psychic disorders with unaltered consciousness or "Dämmerzustand" (twilight state) are being discussed and related to the term "delirium" with its various definitions in recent years.

Topics: How to complete phase II trials faster; stratification of patients in phase II trials, response end points; competition between NCI-sponsored and industry-sponsored phase II trials for patients.

In this issue of Clinical Cancer Research , Townsley et al. report the toxicities they observed in 401 patients enrolled on 19 phase I and II trials of targeted therapeutic agents as part of the National Cancer Institute's (NCI) early therapeutics development program ([1][1]). They compared

Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.

BACKGROUND:Despite recognition of the need to increase the pool of racial/ethnic minority investigators, racial/ethnic minority representation among National Institutes of Health (NIH)-funded investigators remains low. Racial/ethnic minority investigators bring unique perspectives and experiences that enhance the potential for understanding factors that underlie racial/ethnic variation in health and health status. Identification of barriers to successful minority competition for NIH funding and suggestions for strategies to overcome them were obtained from a concept mapping project and a meeting of minority investigators and investigators at minority-serving institutions.METHODS:Concept mapping, a mixed-methods planning approach that integrates common data collection processes with multivariate statistical analyses, was used in this exploratory project. The concept mapping approach generated a series of related "concept maps" that were used for data interpretation and meeting discussions.RESULTS:Barriers to minority investigator competition for NIH funding identified by concept mapping participants include: (1) inadequate research infrastructure, training and development; (2) barriers to development as independent researchers; (3) inadequate mentoring; (4) insensitivity, misperceptions and miscommunication about the specific needs of investigators involved in research with minority communities; (5) institutional bias in NIH policies; (6) unfair competitive environment; (7) lack of institutional support; (8) lack of support for research topics/methods relevant to research with minority communities; and (9) social, cultural and environmental barriers.DISCUSSION:Data from both the concept mapping and the meeting discussions suggest the need to use a multilevel approach to increase minority representation among funded NIH investigators. Specifically, the NIH should use strategies that overcome barriers at the home institution, within NIH and at the investigator level.

Significant disparities exist in cancer incidence among racial and ethnic groups in the United States [(1)][1] . Cancer incidence and mortality rates by gender and race/ethnicity for the most common cancers are shown in Figs. 1[⇓][2] 2[⇓][3] 3[⇓][4] 4[⇓][5] . Blacks have a higher mortality

These are difficult times for the nation's system of protection for human subjects in research.110 On the basis of a series of reports, the Office of the Inspector General of the Department of Health and Human Services concluded that institutional review boards (IRBs) are now forced to “review too much, too quickly, with too little expertise,” and with inadequate resources.6 One consequence is that there is minimal, often perfunctory, review of ongoing research. In addition, IRB members have become disillusioned as a result of both public criticism concerning the perceived failures of the boards and the increasing amount of . . .

PURPOSE:We chose to examine the impact of socioeconomic factors on accrual to National Cancer Institute (NCI)-sponsored cancer treatment trials.PATIENTS AND METHODS:We estimated the geographic and demographic cancer burden in the United States and then identified 24,332 patients accrued to NCI-sponsored cancer treatment trials during a 12-month period. Next, we examined accrual by age, sex, geographic residence, health insurance status, health maintenance organization market penetration, several proxy measures of socioeconomic status, the availability of an oncologist, and the presence of a hospital with an approved multidisciplinary cancer program.RESULTS:Pediatric patients were accrued to clinical trials at high levels, whereas after adolescence, only a small percentage of cancer patients were enrolled onto clinical trials. There were few differences by sex. Black males as well as Asian-American and Hispanic adults were accrued to clinical trials at lower rates than white cancer patients of the same age. Overall, the highest observed accrual was in suburban counties. Compared with the United States population, patients enrolled onto clinical trials were significantly less likely to be uninsured and more like to have Medicare health insurance. Geographic areas with higher socioeconomic levels had higher levels of clinical trial accruals. The number of oncologists and the presence of approved cancer programs both were significantly associated with increased accrual to clinical trials.CONCLUSION:We must work to increase the number of adults who enroll onto trials, especially among the elderly. Ongoing partnership with professional societies may be an effective approach to strengthen accrual to clinical trials.