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Taxol is the first of a new class of anticancer drugs which has focused attention on tubulin and microtubules as critical targets for chemotherapy. Taxol binds to and stabilizes microtubules and is thought to cause cell death by adversely affecting microtubule function during interphase and mitosis. Initial phase I/II studies have shown significant activity in refractory ovarian cancer (with response rates ranging from 21-40%) and in metastatic breast cancer (with response rates of 56-62%). Recent studies have focused on defining optimal taxol schedules and the role of taxol in combination regimens. The first Phase III trial, conducted by the Gynecologic Oncology Group, meeting compared taxol plus cisplatin to standard therapy with cyclophosphamide and cisplatin in women with suboptimally debulked ovarian cancer. Replacement of cyclophosphamide with taxol was associated with a significant improvement in clinical response rate and an increased rate of negative second look laparotomy. Preliminary analysis demonstrated extension of progression-free survival on the taxol arm. Data are not yet sufficiently mature to assess survival. Results of this trial and of three additional phase III trails now underway will define the role of taxol in primary and refractory ovarian cancer.
Significantly, on the strength of these and other NCI-supported clinical trials, taxol was approved by the FDA in 1993 for use in patients with refractory ovarian cancer. This event marked the culmination of successful efforts to address drug supply problems. FDA approval means that taxol, the most active agent discovered int the past 20 years, is now available to all U.S. cancer patients.
Development of New Breast Imaging Technologies
Digital mammography has been identified as the most promising novel technology for early detection of breast cancer. Digital images offer several potential advantages in image quality compared to conventional film-based systems. These include: 1)improved image contrast and resolution at a reduced radiation dose; 2) more efficient image storage and retreival; 3) the potential for electronic image transfer facilitating comparison to previous films and review by expert mammographic readers; and 4) the potential for computer-assisted image interpretation. In March 1992, an interagency agreement between the NCI and the National Aeronautics and Space Administration (NASA) resulted in the establishment of a Working Group for Digital Mammography. At a Workshop held in May, 1993, forty-three proposals received in response to a program announcement entitled "National Digital Mammography Development Group" were reviewed. Thirteen of these were viewed as being "breakthrough" technologies potentially addressing some of the fundamental technologic problems in digital mammography. These included a proposal to develop digital detectors and display systems for the generation of high-resolution, high-field-of-view, high contrast images of the breast, and high performance, low cost networks which can make telemammorgraphy a practical tool. In addition, a number of state-of-the-art machine intelligence-based computer algorithms, which were originally developed for space and military applications, have been identified as novel and promising for image processing and computer-aided diagnosis in digital mammography. It is anticipated that multi-disciplinary teams composed of clinical radiologists, physicists and technical equipment designers from industry and the private sector will be co-funded through a joint NCI/NASA Program Announcement.
Clinical Development of Suramin in the Treatment of Patients With Metastatic Prostate Cancer
Total androgen ablation with the use of leuprolide and flutamide has become routine treatment for patients with metastatic prostate cancer. However, several NCI sponsored trials have established the efficacy of suramin, a prototype heparin-binding polyanionic compound which appears to act at many pivotal points which serve to regulate cell growth, in the treatment of patients with hormone refractory prostate cancer. Of thirty patients with metastic prostate cancer treated with the addition of suramin to leuprolide and flutamide, 70% normalized their elevated prostate specific antigen (PSA) levels. In 50%, PSA levels became undetectable (below 0.5ng/ml). Approximately half of those with measurable soft tissue disease had a response. These results can be compared to three previously reported studies of men with metastatic prostate cancer treated with routine hormonal therapy, 22-50% normalized their PSAs and 0-30% had undetectable PSA levels. In the suramin trial, normalization of PSA was found to be a good predictor of response. None of the 21 patients whose PSA fell to normal has died. Four of the nine patients whose PSA did not fall to normal have died. In this trial, suramin was safely administered in the outpatient setting with few toxicities observed. The results of these studies support the conduct of a larger randomized clinical trial to define the role of suramin with total and androgen ablation.
Initiation of Carcinoembryonic Antigen (CEA) Clinical Trials
Carcinoembryonic antigen (CEA) is one of the most widely studied tumor associated antigens and is expressed by more than 90% of gastrointestinal carcinomas, 50% of breast cancers, and 70% of adenocarcinomas of the lung. While CEA is generally weakly immunogenic in humans and no evidence exists for humoral or cell-mediated immunity to CEA in normal or cancer patients, co-presentation of CEA with a strong immunogen is an approach to inducing an anti-CEA response for tumor therapy. Recent advances in recombinant vaccinia virus technology has permitted the development of clinical grade recombinant CEA-vaccinia constructs and other recombinant CEA vector constructs. A Phase I clinical trial was initiated at the NCI-Navy Medical Oncology Branch in May, 1993. Accrual to this trial which is open to patients with adenocarcinoma of the gastrointestinal tract, breast, or lung has been brisk. To date, fifteen patients have been enrolled, completing the second dose level of this trial. While no efficacy data is available at this point, no significant hematologic or organ function toxicities have been seen.
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