Faculty Bibliography

Preclinical studies have indicated that hydroxyurea leads to enhancement of 5-fluorouracil (5-FU) activity when given after 5-FU. This is presumably due to hydroxyurea's actions resulting in maintaining low levels of deoxyuridine monophosphate pools. The combination of hydroxyurea and 5-FU has been tested in several inconclusive clinical trials in patients with advanced colorectal cancer. However, pharmacodynamic studies have been lacking, and the schedules tested have not usually tried to follow preclinical findings. With the current renewed interest in 5-FU, a role for hydroxyurea as part of its biochemical modulation is worthy of further study.

PURPOSE: The purpose of this study is to evaluate the risk of acute vascular events in patients receiving cisplatin-based chemotherapy for testicular cancer. PATIENTS AND METHODS: A questionnaire assessing cardiovascular toxicity was distributed to all participants in the Testicular Cancer Intergroup study and details of toxicity from the chemotherapy flow sheets were reviewed. Patients with pathologic stage I testicular cancer were registered on to the study and observed after retroperitoneal lymphadenectomy. Patients with pathologic stage II disease were randomized to receive two postoperative courses of adjuvant cisplatin-based chemotherapy or observation. Any patient who had disease recurrence after observation or adjuvant therapy was given four cycles of cisplatin-based chemotherapy. RESULTS: Review treatment-related toxicity for those patients receiving adjuvant chemotherapy (n = 97) or chemotherapy for recurrent disease (n = 83) showed no cases of acute cardiovascular toxicity. The median follow-up period after study enrollment was 5.1 years; 459 questionnaires were mailed and 270 were returned. The percent return was equal among the observed adjuvant and recurrent groups (59%, 54%, and 64%). There was a significant increase in the incidence of extremity paresthesias in the two groups receiving chemotherapy. Fatal myocardial infarction was reported in two patients in the observation group and one nonfatal infarction was reported in the adjuvant treatment group. No patient in any group reported an incidence of stroke. Three patients in the observation group and one patient in the recurrent group experienced a thromboembolic event. CONCLUSION: Despite sporadic case reports suggesting a causal association between chemotherapy for testicular cancer and acute vascular events, this retrospective analysis provides no evidence of an increased risk for subsequent cardiovascular disease in this patient population.

Teniposide and etoposide are third-generation semi-synthetic derivatives of epipodophyllotoxin. Following the initial clinical introduction of teniposide in the 1970s, investigations focused almost exclusively on its analogue, etoposide, because of its formulation, which was felt to have advantages in addition to oral administration. Despite consistently inadequate dosing and scheduling, early phase I and II trial results with teniposide were promising, and current trends encourage a second look. The substantial antitumor activity of teniposide is comparable with that of etoposide, and clinical interest was rekindled when it was shown to have considerable activity against small cell lung cancer (SCLC). In view of the inadequacy of early trials and the premature cessation of clinical study, it is recommended that teniposide be reevaluated for its activity against malignant lymphomas, Hodgkin's disease, leukemias, and SCLC, against all of which its early results were encouraging. In addition, consideration should be given to its activity against brain tumors, neuroblastomas and other childhood solid tumors, and ovarian cancer; its potential value against gastric, hepatocellular, breast, and bladder cancers also should be investigated. Other areas that warrant further study include elucidation of the exact mechanism of action of teniposide, its role in both single- and multiple-agent chemotherapeutic regimens, and resolution of its optimal dose and schedule. Finally, it is suggested that with new routes of administration and improved formulations, teniposide may be expected to play a significant role in the treatment of malignant lymphomas, SCLC, and pediatric lymphocytic leukemia and neuroblastoma.

Nineteen patients with ovarian cancer and minimal residual or persistent disease who were treated with cisplatin or carboplatin-based intraperitoneal (IP) regimens had distribution studies of IP contrast and computerized tomography prior to and during treatment. The distribution pattern was assessed retrospectively and scored for the presence of contrast in each of eight regions: the under surface of right and left diaphragms, the right and left paracolic gutters, the lesser omental sac, the intramesenteric region and the true and false pelvis. Assigning a point to each region with adequate distribution, we classified 10 patients to an excellent pattern (greater than or equal to 7 of 8 regions), 6 to a good pattern (5 to less than 7 regions), and 3 to an inadequate distribution pattern (less than 5 regions). Serial studies were performed in 8 patients after more than 4 cycles of IP therapy. In these patients, all of whom were tolerating treatment without progression, the distribution remained virtually unchanged for those with excellent distribution. One of three with good distribution manifested inadequate distribution on repeat study, and one of two with inadequate distribution improved to show a good pattern. In this small study there was no correlation of distribution patterns with plasma CA-125 at onset of IP treatment and prior surgical procedures or placement of the catheter tip. However, three patients with unsatisfactory patterns had procedures consisting of catheter placement only rather than formal reassessment laparotomies for ovarian cancer. Since satisfactory IP distribution may be required for obtaining a therapeutic advantage from IP therapy, methods for its assessment must be developed.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of carboplatin in cervical and endometrial cancers is being assessed through clinical trials. Preliminary results indicate some activity against both of these gynecologic tumors. Carboplatin is also being integrated into combination regimens with other active drugs. In the treatment of cervical cancer, it is used as part of combined-modality regimens prior to radiotherapy. Patients have shown better subjective tolerance to carboplatin than to cisplatin. This finding may facilitate the widespread implementation of carboplatin-based combinations.

The treatment of advanced breast cancer has undergone relatively little change in the past decade. Reasons for such a static situation are the sobering realization that even effective chemotherapeutic regimens have had a minor impact on survival, and the paucity of new effective agents that have been introduced since initial combination treatments. Based in part on this lack of progress, in recent years dose-intensification in search of a curative strategy has been widely adopted. Its role remains to be defined, but ultimately it is likely to be relegated to situations where tumor burdens have been effectively reduced. This reduction in burden may not currently be feasible in many advanced presentations. Outpatient efforts will therefore focus on the following: 1) employing single agents optimally (e.g. infusion 5-fluorouracil), 2) using regimens which integrate new drugs with activity (e.g. taxol), and 3) testing measures which may improve the quality of life (e.g. bisphosphonates in the presence of bone metastases). Although one cannot approach the treatment of advanced breast cancer with the (misplaced) optimism of two decades ago, the expanded armamentarium currently available should lead to a more rational application of chemotherapy. Treatments will increasingly be based on the biology of the cancer, and on the therapeutic index and action of the drugs.

From June 1988 to November 1990 the Southwest Oncology Group initiated nine protocols for the phase II evaluation of recombinant human tumor necrosis factor alpha (rhuTNF alpha) in cancer patients. Patients with diverse metastatic malignancies including breast, colon, gastric, pancreatic, endometrial, and bladder cancers, as well as multiple myeloma and various sarcomas received 150 micrograms/m2 of rhuTNF alpha daily for 5 days every other week. Of 147 patients entered in the study, 127 were eligible and were evaluated for toxicity and response. Of 124 patients known to have completed treatment, 92 (74%) went off study for progression, 21 (17%) for toxicity, and 12 (10%) for other causes, mainly that of worsening medical condition. Thirteen percent of patients experienced grade 4 or fatal toxicity. The most serious toxicities were pulmonary failure and coagulopathies. The predominant grade 3 toxicities were symptomatic (chills, fever, malaise, headache, myalgia, and nausea or vomiting). Only one partial remission was seen in a patient with metastatic bladder cancer lasting 4 months (rate 0.8%, exact 95% confidence interval 0-4%). At the study dose and schedule, rhuTNF alpha does not appear to have significant antitumor activity. The biological basis for this finding is discussed.