Background. Treatment of the symptoms of bone metastases currently involves the use of narcotic medication, radiation therapy, or hormonal therapy. Pamidronate disodium, a bisphosphonate, may prove helpful in the palliative treatment of bone metastases in patients with breast cancer as demonstrated in this multicenter, dose-ranging trial.Methods. Ambulatory female patients age 18 years or older with breast cancer metastatic to bone and a life expectancy of at least 3 months were eligible for the study. Bone metastases were confirmed by bone scan or bone survey within 6 months of enrollment. Sixty-one patients were treated as outpatients and were randomized to receive one of four intravenous pamidronate regimens for 12 weeks: 30 mg administered every 2 weeks, 60 mg every 4 weeks, 60 mg every 2 weeks, or 90 mg every 4 weeks. The primary efficacy parameter for this study was pain score. The change from baseline in pain score was determined for each patient at each study visit and at endpoint, defined as the last postbaseline evaluation for each patient before or at week 12. Secondary efficacy variables included narcotic scores, urinary calcium/creatinine and hydroxyproline/creatinine ratios, serum osteocalcin and bone alkaline phosphatase concentrations, and bone lesion (radiologic) response.Results. At 3 months, the regimens of 60 mg every 4 weeks, 60 mg every 2 weeks, and 90 mg every 4 weeks resulted in significant reduction in bone pain beginning by week 6 of treatment. The regimen of 30 mg every 2 weeks was not effective. Narcotic use, as reflected by narcotic scores, did not parallel the pain scores, because there was little evidence of any effect for any of the treatment groups. Reduction in bone pain was accompanied by decreases in urinary calcium/creatinine and hydroxyproline/creatinine ratios, and bone alkaline phosphatase concentrations. Side effects of pamidronate were mild and transient. Radiographic changes consistent with healing of lytic lesions were observed in 15 patients (25%).Conclusion. Intravenous pamidronate is a well tolerated treatment that produced significant relief of bone pain in the majority of patients with metastatic breast cancer at the three highest doses tested.

One hundred patients were entered on a randomized prospective protocol to evaluate the effectiveness of hepatic resection of single as well as multiple hepatic metastases from colorectal primaries in combination with continuous hepatic artery infusion (CHAI) of fluorodeoxyuridine (FUDR) via the implantable pump (Infusaid, Intermedics Infusaid Inc., Norwood, MA). The eight patients with single metastases were randomized to hepatic resection alone (three patients) or hepatic resection plus CHAI (five patients). The 22 patients with resectable multiple metastases were randomized between receiving CHAI only (12) or CHAI after resection of all metastases (10). Patients who had positive portal lymph nodes (14) were all treated with CHAI. Patients with unresectable metastases (31) were randomized between intravenous 5-fluorouracil or CHAI of FUDR. FUDR was alternately infused every 2 weeks at a dose of 0.1 mg/kg/24 hour escalated to .3 mg/kg/24 hour with heparinized saline as the alternative infusate. The median follow-up of all patients was 20 months. All patients with multiple resectable metastases had at least a partial response (PR) to the CHAI (PR defined as greater than or equal to 50% decrease of the sum of the products of the diameters of the lesions measured on computerized axial tomography scans), and four patients given CHAI only had no metastases in the liver on relaparotomy. Patients with resection and CHAI had a better survival than patients with CHAI only; however, the difference was not significant. Patients with positive portal nodes and CHAI had a lower PR (36%) than patients with unresectable disease treated with CHAI (52%). Patients with positive portal nodes or metastatic disease outside of the liver did significantly worse than patients with unresectable disease treated with CHAI.

Sixty-five patients with hepatic metastases from colorectal primaries were studied in a prospective randomized fashion. The five patients with solitary metastases all had resection of metastases and 50% were randomized to pump therapy. Of the 16 patients with multiple resectable metastases, 7 had pump only and 9 had resection plus pump. Although the difference was not significant, there was a trend of improved survival for the patients with resection plus pump. For the patients with unresectable disease, those patients with positive portal nodes had poor survival matching those patients with extra hepatic metastases. Patients with unresectable disease treated with pump had a 73% therapeutic response rate and a median survival of 22 months. Significant complications included chemical hepatitis and biliary stenosis. The long-term efficacy of continuous hepatic artery infusion versus the hazards of treatment and the financial cost will need further investigation.

In order to determine whether a simultaneous infusion of N-(phospho-n-acetyl)-L-aspartic acid (PALA) was able to increase the rate of antitumor response to 5-fluorouracil (5-FU), a pilot study was conducted. Of 10 evaluable patients with previously drug-untreated colorectal carcinoma, there were only two partial responses, lasting 2.3 and 1.6 months. No partial responses were observed in three evaluable patients with soft tissue sarcomas. The dose-limiting toxicity was dermatitis. The simultaneous infusion of PALA and 5-FU is not likely to produce a high number of antitumor responses of long duration in patients with colorectal carcinoma.