Phase II evaluation of continuous-infusion 5-fluorouracil, leucovorin, mitomycin-C, and oral dipyridamole in advanced measurable pancreatic cancer: a North Central Cancer Treatment Group Trial.

At present there remains a need for more effective systemic therapy in advanced pancreatic cancer. Some studies have suggested that infusional chemotherapy schedules and biomodulation of 5-fluorouracil (5-FU) may improve the therapeutic outcome in advanced colon cancer. One such regimen that uses continuous infusion 5-FU, weekly leucovorin, daily dipyridamole, and intermittent mitomycin-C has activity in both colon and unresectable pancreatic carcinoma. The intent of this trial was to test the effectiveness of this four-drug regimen in advanced pancreatic cancer. Patients received 5-FU 200 mg/m2 daily by continuous infusion, leucovorin 30 mg/m2 IV weekly, mitomycin-C 10 mg/m2 day 1, and dipyridamole 75 mg orally four times daily for 5 weeks. After a 1-week break, treatment cycles were repeated every 6 weeks. Eligibility included biopsy-proven advanced measurable pancreatic cancer, Eastern Cooperative Oncology Group performance status 0 and 2, and no prior systemic chemotherapy. Of 46 evaluable patients, 9 partial responses and 1 complete tumor response were seen, for an overall response rate of 22% (95% confidence interval 11-36%). The median survival in the group of 50 patients registered to this trial was 4.6 months, with a range of 0.33 to 40.2 months. Toxicity was manageable, with the most common toxicities (> or =grade III National Cancer Institute Common Toxicity Criteria) being anorexia (13%), stomatitis (17%), and hand-foot syndrome (13%). Of note, little severe hematologic toxicity and no significant headaches were reported. Although some patients did respond, the therapeutic results are not encouraging enough to take this regimen to phase III testing.

Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189.

PURPOSE: The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P

Phase I study of 5-fluorouracil administered by protracted venous infusion, leucovorin, and pelvic radiation therapy.

BACKGROUND: This study was designed to assess the toxicity of pelvic radiation therapy, 5-fluorouracil (5-FU) administered by protracted venous infusion, and leucovorin. METHODS: Pelvic radiation therapy consisted of 50.4-54 gray (Gy) administered in 28-30 fractions. Systemic treatment consisted of leucovorin (10 mg daily) administered orally and protracted venous infusion of 5-FU. The initial daily 5-FU dose was 150 mg/m(2). Dose escalations were planned in increments of 25 mg/m(2). RESULTS: Forty eligible patients were registered, of whom 37 were evaluable for chemoradiotherapy-related toxicity. Grade 3 or 4 toxicity secondary to radiation therapy, protracted venous infusion of 5-FU, and leucovorin occurred in 2 of 17 patients at a daily 5-FU dose of 150 mg/m(2), in 5 of 10 patients at a daily 5-FU dose of 175 mg/m(2), and in 5 of 10 patients at a daily 5-FU dose of 200 mg/m(2). Diarrhea was dose-limiting in 7 of 8 patients with Grade 4 toxicity. Venous thrombosis, a treatment-related complication not directly related to chemotherapy or radiation therapy, occurred in 5 of the 40 patients entered into this study. Four thromboses occurred at the site of a central catheter. No thrombotic complications occurred in the last 7 patients, who were given warfarin orally (1 mg daily) during treatment. CONCLUSIONS: Toxicity due to radiation therapy, protracted venous infusion of 5-FU, and leucovorin when 5-FU is given daily at a dose of 150 mg/m(2) is similar to that observed in current chemoradiotherapy regimens for patients with rectal carcinoma. This regimen will be considered as a possible investigational treatment arm of a future trial of adjuvant therapy for rectal carcinoma patients.

A randomized trial of megestrol acetate with or without premarin in the treatment of potentially responsive metastatic breast cancer. A Study of the Eastern Cooperative Oncology Group (E2185).

BACKGROUND: Human breast cancer cells in vitro exhibit increased levels of progestin receptors (PgR) after brief exposure to physiologic concentrations of estrogens. Prior clinical studies have positively correlated the responsiveness of metastatic breast cancer to progestin therapy with the level of PgR in the tumor cells. METHODS: These observations were used as the scientific basis for a randomized clinical trial by the Eastern Cooperative Oncology Group (ECOG) to compare the effectiveness of megestrol acetate (MEG) alone in a daily dose of 160 mg with MEG alternated with premarin in a dose of 1.25 mg/day on the first 3 days of a 14 day cycle (PRE/MEG). From 1985 through 1989, 266 eligible and fully evaluable patients were randomized to 1 of the treatment arms and accrued to this trial. All patients were postmenopausal with biochemical estrogen cytosol protein receptor (ER) positive (> or = 10 fm/mg) tumors. The treatment groups were balanced with respect to performance status, number of involved organ systems, and PgR levels. RESULTS: Forty-five of 135 (33%) (95% confidence interval [CI], 25-42%) patients receiving MEG experienced a partial (PR) or complete (CR) response. Thirty-one of 131 (23%) (95% CI, 17-32%) patients receiving PRE/MEG achieved a PR or CR. Survival was not influenced by treatment selection. However, median time to progression was seven months for patients receiving MEG and four months for the group receiving PRE/MEG (P = 0.03). The treatment failure hazard rate was higher for patients with a short disease free interval after primary treatment of the breast cancer, poor performance status, non-white race, and visceral disease. Survival was negatively impacted by short disease free interval, administration of prior radiation therapy, prior treatment for metastatic disease, and hepatic involvement. CONCLUSIONS: Sequential treatment with premarin and megestrol acetate is not superior to treatment with megace alone in potentially hormone responsive patients with advanced breast cancer.

Results of combined modality therapy for patients with anal cancer (E7283). An Eastern Cooperative Oncology Group study.

BACKGROUND: This prospective study assessed combined modality therapy of patients with International Union Against Cancer classification T1-4 N0 M0 anal cancer. METHODS: Protocol therapy consisted of a dose of 4000 cGy to the pelvis, anus, and perineum, followed by a 1000-1300 cGy boost. Infusions of 5-fluorouracil and mitomycin-C were administered when radiation therapy began. A second infusion of 5-fluorouracil was administered 28 days later. Biopsy was performed 6-8 weeks after completion of treatment. Positive biopsy findings resulted in abdominal-perineal resection. RESULTS: Survival at 7 years for 50 eligible patients was 58%. White patients and those with favorable performance status had significantly better survival. Of the 46 patients evaluable for response, 34 had a complete response, 11 had a partial response, and 1 had no response. Seven-year survival for partial responders was 53%. Freedom from locoregional progression was 80% at 7 years. CONCLUSION: Treatment with a combination of chemotherapy and radiation therapy is effective for patients with anal cancer. The investigation of methods of improving therapy is warranted.

Clinical trials in the community. The community clinical oncology program experience.

In 1983, the National Cancer Institute initiated the community clinical oncology program (CCOP), the goal of which was to hasten the adoption of state-of-the-art cancer medicine in community-based institutions. The strategy adopted was to link community oncologists to major cancer centers and research bases for the conduct of clinical trials. Since the program was initiated, a significant amount of literature has been developed, providing insight into the operation and success of the program. These reports have been combined with experience of the author, a principal investigator of an established CCOP, in an effort to characterize the critical features of the program. Experience to date indicates that CCOPs have been successful in accruing patients to cancer-treatment clinical trials, contributing approximately one third of patients placed in investigational protocols. Since 1987, CCOPs have been required to participate in nontreatment-related research in cancer prevention, detection, and mitigation of cancer symptoms, or cancer control research. After a slow beginning, both the research bases and CCOPs have accumulated experience in the development of and accrual of patients in cancer control protocols. This review suggests that CCOPs, as they mature, will fulfill their goal as an important mechanism for the transfer of technology and the conduct of clinical research.

Randomized placebo-controlled evaluation of hydrazine sulfate in patients with advanced colorectal cancer.

PURPOSE: Hydrazine sulfate is a controversial agent that was originally studied in cancer patients approximately 20 years ago. Based on a series of recent trials that suggested that this drug might have utility in cancer patients, we conducted this study. PATIENTS AND METHODS: Patients with metastatic colorectal cancer were randomized to receive hydrazine sulfate or placebo in a double-blinded manner. Protocol patients did not concurrently receive any other systemic antineoplastic treatment. RESULTS: There were 127 assessable patients entered onto this clinical trial. Data from the study showed trends both for poorer survival and for poorer quality of life (QL) in the hydrazine group. There were no significant differences in the two study arms with regard to anorexia or weight loss. CONCLUSION: This trial failed to demonstrate any benefit for hydrazine sulfate.

Increasing physicians' and nurses' compliance with treatment guidelines in cancer care program.

Three community hospitals in Toledo, Ohio, formed a consortium with the common goal of improving the quality of cancer care in the community. Procedural guidelines were established for physicians, nurses, and allied health professionals to use in the diagnosis and treatment of 19 types of cancer. In this paper, the authors report the effect of the use of the guidelines on the care of patients with breast, colon, and non-small-cell lung cancers. Audits of patient records revealed an increase over time in the percentage of recommended cancer care procedures that were complied with. Factors that may have contributed to this success included the hospitals' commitments to the program at the professional and administrative levels, the ready availability of the guidelines during the treatment process, and a mandatory component requiring documented classification of the stage of the cancer.

Adriamycin, bleomycin, and CCNU as effective induction chemotherapeutic agents in advanced squamous cell carcinoma (COG Protocol 7333).

Twenty-six member institutions of the Central Oncology Group entered 154 patients in this two-armed, phase III study comparing the effects of adriamycin, bleomycin, and CCNU against a variety of squamous cell carcinomas. The combination of adriamycin and bleomycin produced a 43% overall response rate in primary tumors of the head and neck, which included two complete responses. This compares favorably to the results obtained with methotrexate and other agents previously reported. The combination of adriamycin and bleomycin will probably be the most useful for induction chemotherapy because both drugs have cumulative toxicities and the duration of response to this combination is short.