Evaluation of continuous infusion suramin in metastatic breast cancer: impact on plasma levels of insulin-like growth factors (IGFs) and IGF-binding proteins.

Suramin represents a new class of antitumor drugs that targets growth factor networks. In this Phase II trial, suramin was administered by continuous infusion to 10 patients with advanced breast cancer. The target level of 280 microgram/ml suramin was achieved in a median of 10 days; toxicities in this patient group were low. We monitored the insulin-like growth factor (IGF) network in these patients because of the previously defined growth-promoting role of the IGFs in breast cancer. Plasma levels of total IGF-I and total IGF-II showed variable responses to suramin with median decreases of 24 and 23%, respectively, for the 10 patients; for total IGF-I levels, this did not reach statistical significance. On the other hand, free IGF-I plasma levels were consistently and dramatically increased (over 250%) after suramin infusion. IGF-binding proteins (IGFBPs), modulators of IGF bioavailability, were also measured. Levels of IGFBP-3, the major carrier of IGFs in the circulation, were decreased 21% after suramin treatment when measured by immunoradiometric assay. However, the majority of the plasma IGFBP-3 remaining after suramin was not the intact high-affinity IGF-binding form but rather a 30-kDa fragment with markedly reduced affinity for IGF-I. IGFBP-3 protease activity was evident in the plasma of 3 of 10 patients after suramin. Measurements of plasma IGFBP-1, IGFBP-2, and IGFBP-4 revealed no significant changes in response to suramin. The dramatic increase in active free IGF-I seen after suramin raises concern and underscores the importance of measuring relevant biomarkers in clinical trials.

Breast conservation therapy for invasive breast cancer: a review of prior trials and the Mayo Clinic experience.

OBJECTIVE: To assess the role of breast conservation therapy in the management of early-stage invasive breast cancer. DESIGN: We reviewed the results of previously published trials and summarized 165 cases of breast conservation surgical procedures and irradiation at the Mayo Clinic between January 1979 and September 1989. MATERIAL AND METHODS: From the prior clinical trials, the criteria for selection of patients, the surgical and radiation techniques used, the complications of treatment, the cosmetic results, and the follow-up assessment and survival were analyzed. The 165 Mayo patients were also characterized, and their results were described. RESULTS: Breast conservation therapy consists of excision of the primary tumor followed by irradiation. A coordinated multidisciplinary approach should be used for selection of patients. Several large-scale clinical trials have demonstrated that breast conservation therapy is an appropriate option for most women with early-stage breast cancer and provides tumor control and survival rates equivalent to mastectomy. With a collaborative treatment program and judicious application of contemporary standards of practice, a good-to-excellent cosmetic outcome can be achieved in most patients, and the risk of treatment-related sequelae is minimal. The Mayo Clinic experience with breast conservation therapy is consistent with these observations and compares favorably with other institutional and clinical trial results. CONCLUSION: Patients should be fully educated about the options for primary management of early-stage breast cancer because the selection of therapy may profoundly influence psychologic adjustment and acceptance of the treatment program.

Evaluation of ifosfamide plus mesna as first-line chemotherapy in women with metastatic breast cancer.

Ifosfamide is an oxazaphosphorine analogue of cyclophosphamide with proven activity in breast cancer but substantial urotoxicity. The introduction of mesna as a uroprotective agent provided a stimulus for reexamination of ifosfamide for therapy of women with metastatic breast cancer. Twenty women with measurable (18 patients) or evaluable (2 patients) disease were entered into a phase II clinical trial of ifosfamide plus mesna as first-line chemotherapy. Ifosfamide was administered i.v. at a dose of 1,800 mg/m2 in 1 L D5W over 2 h on five consecutive days. Mesna was administered i.v. at a dose of 400 mg/m2 over 15 min immediately before and 1 h after ifosfamide, and then every 4 h for three more doses. The last three doses could be given either i.v. or orally. The planned cycle length was 28 days. Three patients (15%), all with measurable disease, achieved a partial response (95% confidence interval: 3 to 38%). Median time to progression was 137 days and median survival was 407 days. Toxicities included cumulative myelosuppression and substantial nausea and emesis. Four patients were removed from treatment because of toxicity alone and a fifth refused further therapy. We conclude that ifosfamide, plus mesna, as given in this protocol has definite but limited antitumor activity and poor tolerability.