Theoretical and practical application of traditional and accelerated titration Phase I clinical trial designs: the Wayne State University experience.

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.

How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials.

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.

New cisplatin analogues in development. A review.

Cisplatin was discovered to have cytotoxic properties in the 1960s, and by the end of the 1970s it had earned a place as the key ingredient in the systemic treatment of germ cell cancers. Since the early seminal work in the preclinical and clinical development of this drug, several thousand analogues have been synthesised and tested for properties that would enhance the therapeutic index of cisplatin. About 13 of these analogues have been evaluated in clinical trials, but only one (carboplatin) has provided definite advantage over cisplatin and achieved worldwide approval. However, carboplatin has afforded benefit only in reducing some cisplatin toxicities; it has not enlarged the spectrum of platinum-sensitive cancers, nor has it proved active in cisplatin-resistant cancers. The major obstacle to the efficacy of cisplatin or carboplatin is platinum resistance, either innate or acquired. The mechanisms of this resistance have been under intense study, and many of the cisplatin analogues synthesised in the past decade have been designed specifically with the hope of overcoming platinum resistance. The mechanism of the cytotoxic activity of platinum complexes has also been studied intensely. Recently synthesised analogues have been designed to interact with DNA in a manner different from cisplatin and carboplatin, with the desire of finding new structures with a superior or wider spectrum of antitumor efficacy. Most recently, water soluble platinum complexes that retain antitumour activity, but that can be effectively absorbed after oral administration, have been synthesised with the goal of improving patient quality of life. Nine platinum analogues are currently in clinical trials around the world (ormaplatin [tetraplatin], oxaliplatin, DWA2114R, enloplatin, lobaplatin, CI-973 [NK-121], 254-S, JM-216 and liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) [LNDDP]). Some of these analogues only represent attempts to reduce cisplatin toxicity and/or allow administration without forced hydration and diuresis, which carboplatin already does. Others are 'third generation' complexes shown to have limited or no cross-resistance with cisplatin in preclinical studies. They are being tested clinically with particular attention to this highly desirable property.(ABSTRACT TRUNCATED AT 400 WORDS)

Intraperitoneal chemotherapy for women with epithelial ovarian cancer.

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.