Gallium nitrate inhibits calcium resorption from bone and is effective treatment for cancer-related hypercalcemia.

Approximately two-thirds of patients who receive the anticancer drug gallium nitrate develop mild hypocalcemia. To evaluate the mechanism of drug-induced hypocalcemia, we tested the effects of gallium nitrate upon in vitro release of 45Ca++ from explanted fetal rat bones. The drug significantly inhibited 45Ca++ release in response to stimulation with both parathyroid hormone and a lymphokine preparation with osteoclast activating factor activity. The inhibitory effects on bone resorption were both time- and dose-dependent. Later, in a pilot study, we treated 10 patients who had cancer-related hypercalcemia with gallium nitrate administered by continuous infusion. All patients responded by a reduction of total serum calcium to normal or subnormal concentrations (13.8 +/- 1.05 mg/dl, mean +/- SD pretreatment, to 8.03 +/- 1.03 mg/dl, mean posttreatment nadir). Our results indicate that gallium nitrate effectively treats cancer-related hypercalcemia and that it probably acts by inhibiting calcium release from bone.

Homoharringtonine: an effective new drug for remission induction in refractory nonlymphoblastic leukemia.

Homoharringtonine (HHT) is a new plant alkaloid originally isolated in the People's Republic of China. Preliminary studies have suggested antitumor activity in several neoplastic diseases. We treated 49 patients with relapsed or resistant acute leukemia with escalating doses of homoharringtonine administered by continuous infusion. Three dose levels were examined: 5 mg/m2 for seven days, 7 mg/m2 for seven days, and 5 mg/m2 for nine days. Of 28 patients with acute nonlymphoblastic leukemia who received cumulative doses of 45 to 49 mg/m2, seven patients (25%) achieved complete remission. Four of these remissions occurred in a subset of ten patients previously resistant to two or more induction attempts with conventional chemotherapy. There were no remissions in three patients with secondary leukemia or in seven patients with acute lymphoblastic leukemia. Reversible hypotension, fluid retention, diarrhea, and tumor lysis syndrome were the major toxic effects of this treatment. Our results indicate that homoharringtonine is an effective new drug for the treatment of acute nonlymphoblastic leukemia and that this drug does not share cross-resistance with conventional antileukemic agents. The recommended dose is 5 mg/m2/d administered by continuous infusion for nine days.

Sequential inhibition of polyamine synthesis. A phase I trial of DFMO (alpha-difluoromethylornithine) and methyl-GAG [methylglyoxal-bis(guanylhydrazone)].

Both DFMO and methyl-GAG inhibit sequential enzymatic reactions in the pathway of polyamine biosynthesis. Since polyamines may be important factors in proliferation of cancer cells, we initiated a phase-I study of these agents in patients with advanced cancer. DFMO was given by mouth at a constant daily dose of 4 g/m2 starting on day 1 of the treatment protocol. The dose of methyl-GAG ranged from 200 to 700 mg/m2 administered IV every 2 weeks beginning on day 4. Twenty-two patients were entered into the protocol. Toxic reactions to this therapy were dose-related and included nausea, fatigue, diarrhea, and myelosuppression. One patient with colon cancer experienced a greater than 50% decrease in measurable disease but developed severe myelotoxicity. While DFMO was well tolerated, the combination of drugs appeared to cause substantially more hematologic and gastrointestinal toxicity than encountered during our recent experience with methyl-GAG used alone. We suggest that future studies of this drug combination carefully evaluate levels of polyamines and inhibition of enzymatic activity to minimize toxicity.

Chemotherapy of metastatic sweat gland carcinoma. A retrospective review.

Sweat gland carcinoma (SGC) is a rare malignancy of the skin. though many patients with SGC die of disseminated metastases, little is known regarding the value of systemic chemotherapy for this disease. We reviewed the records of 20 patients with metastatic SGC who were treated with chemotherapy at Memorial Hospital between 1968 and 1983. A large variety of drugs were given. Although only a few patients were treated with any given regimen, metastatic SGC appears to be poorly responsive to a wide variety of chemotherapeutic regimens. Five major responses were observed in 30 chemotherapy trials performed in 17 patients with measurable/evaluable disease. No patient responded to single agent therapy alone. In this small group of patients, SGC appears to be a relatively chemotherapy resistant tumor. Larger, group-wide or inter-group trials are needed to prospectively evaluate the use of chemotherapy in this disease. Doxorubicin and cyclophosphamide, the two drugs used most commonly in those combinations where responses were seen, appear to be reasonable choices for initial treatment of patients with metastatic disease. Our review does not provide data to support the empiric use of chemotherapy in an adjuvant setting.

Fatal acute tumor lysis syndrome with metastatic breast carcinoma.

A 53-year-old woman presented with an extensively metastatic and rapidly growing breast adenocarcinoma, markedly elevated lactate dehydrogenase, and mildly elevated blood urea nitrogen. She received 5-fluorouracil, doxorubicin, and cyclophosphamide. Eighteen hours after chemotherapy she was noted to have hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute renal failure. She experienced cardiac arrest and died 72 hours after receiving chemotherapy. A postmortem liver biopsy revealed adenocarcinoma undergoing necrosis. This case represented the acute tumor lysis syndrome that occurred after chemotherapy of breast carcinoma. Patients with metastatic breast carcinoma and similar presentations should be considered for prophylactic therapy with allopurinol and hydration before chemotherapy.

Phase I trial of homoharringtonine administered as a 5-day continuous infusion.

Homoharringtonine (HHT) has substantial cytotoxic activity against cell lines of experimental tumors. Moreover, the drug has been used extensively in the People's Republic of China for the treatment of patients with acute leukemia. Since rapid injections of HHT can produce serious hypotension and cardiac arrhythmias, we evaluated HHT administered as a continuous infusion for 5 days in patients with advanced cancer. Thirty-one patients were treated with HHT at doses which ranged from 0.2 to 3.75 mg/m2/day. Myelosuppression (both leukopenia and thrombocytopenia) was the dose-limiting toxic reaction. Platelet recovery was delayed in five patients; the median time to platelet nadir was 31 days in patients treated at the highest dose level. Sinus tachycardia occurred frequently, but the relation of this effect to drug administration was uncertain. Serious cardiac arrhythmias and hypotension were not observed using this schedule. We conclude that HHT can be safely administered as a continuous infusion. A daily dose of 3.25 mg/m2 x 5 days is recommended for phase II studies.

Salvage chemotherapy of advanced lymphoma with investigational drugs: mitoguazone, gallium nitrate, and etoposide.

Patients with advanced lymphoma who relapse from intensive first-line combination chemotherapy generally have a very poor prognosis. The use of investigational drugs which lack cross-resistance to agents commonly used for initial therapy represents an important approach to the management of such patients. Based upon our prior experience, we developed a protocol which employed a combination of three new agents. Mitoguazone (600 mg/m2) was administered on Days 1 and 10; etoposide (100-125 mg/m2) was administered on Days 2, 3, and 4; and gallium nitrate (300 mg/m2/day) was administered as a continuous iv infusion over 24 hours on Days 1-7. Treatment cycles were repeated every 3-4 weeks pending tolerance to toxic reactions. Forty-two patients are evaluable for response (35 with non-Hodgkin's lymphoma and seven with Hodgkin's disease). All patients had received extensive prior treatment (median of two previous chemotherapy regimens). Less than one-half of patients had achieved complete remission (CR) with previous therapy. Twenty-two patients (52%) showed major antitumor responses (five CR, 17 partial). All patients who achieved CR had diffuse large cell lymphoma. Two patients in CR relapsed in the CNS. The median duration of response for patients who achieved partial response was 4 months (range, 1-11+). Major toxic reactions included myelosuppression, optic neuritis, mucositis, and corneal keratitis or conjunctivitis. This combination of experimental agents has major therapeutic activity in patients with advanced, resistant lymphoma. Optimal application of these drugs may be obtained by use as one arm of an intensive program of alternating non-cross-resistant regimens.

Treatment of patients with advanced malignant lymphoma using gallium nitrate administered as a seven-day continuous infusion.

Previous trials of gallium nitrate (NSC-15200) showed that bolus administration produced dose-limiting nephrotoxicity without substantial antitumor activity. As an effort to increase the therapeutic index of this compound and to establish a satisfactory out-patient schedule, the authors evaluated the effects of gallium nitrate administered as a continuous infusion in patients with advanced malignant lymphoma. In an initial Phase I trial, four dose levels which ranged from 200 to 400 mg/m2/day in 27 patients were studied. Nausea which impaired oral hydration was found to be dose-limiting. A dose of 300 mg/m2/day was chosen for extended Phase II evaluation and 37 additional patients were entered into the study at that dose level. Overall, 16 of 47 patients (34%) who had bi-dimensionally measurable parameters of disease achieved major antitumor responses (six of 15 with diffuse "histiocytic" lymphoma, five of ten with diffuse poorly-differentiated lymphocytic lymphoma, two of five with nodular poorly-differentiated lymphocytic lymphoma, and three of 17 with Hodgkin's disease). The median duration of response was 2.5 months. Only 8% of patients who received 300 mg/m2/day developed an increase in serum creatinine concentration greater than 1.1 mg/dl over baseline values. Hypocalcemia occurred in two-thirds of patients. Other toxic effects, including paresthesiae, diarrhea, and hearing loss, were noted in less than 5% of patients. There was minimal myelosuppression. The authors conclude that gallium nitrate administered as a continuous infusion for seven days at 300 mg/m2/day is well-tolerated and effective treatment for patients with advanced malignant lymphoma. Outpatient administration using portable infusion pumps is safe and practical. Further evaluation of the drug administered as a constant infusion is indicated in patients with other neoplastic diseases.

Hodgkin's disease presenting with rectal symptoms in a homosexual male. A case report and review of the literature.

A 33-year-old homosexual man presented with complaints of rectal discharge and tenesmus. There was no evidence of organomegaly or lymphadenopathy. Biopsy of a rectal mass revealed Hodgkin's disease. The literature of rectal Hodgkin's disease is reviewed, and the possible relationship of this unusual case to the recent outbreak of other unusual malignancies in homosexual males is discussed.

Cisplatin and bleomycin in the treatment of esophageal carcinoma. A final report.

During the period from September, 1976 to June, 1979, 70 patients with locoregional or extensive epidermoid carcinoma of the esophagus were treated with the two-drug combination of cisplatin and bleomycin (DB). For the 43 patients with locoregional disease (LRD), DB was used prior to surgery and/or radiation therapy; it was the primary treatment for 27 patients with extensive disease (ED). The major objective response rates [complete remission (CR) and partial remission (PR)] to DB for the LRD and ED groups were 14% and 17%, respectively, for an overall response rate of 15%. For the LRD group, the minimum follow-up was 42 months; four patients (10%) remain alive and free of disease. The median survival of 34 patients treated with DB preoperatively was 10 months, which did not differ significantly from that of a historic control group receiving preoperative radiation therapy. The median duration of response for ED patients was 6 months, and the median survival for the entire ED group was 4 months. DB alone had only modest activity in epidermoid carcinoma of the esophagus.

Metabolic effects of gallium nitrate administered by prolonged infusion.

Gallium nitrate was recently found to be effective treatment for resistant cancer-related hypercalcemia. In vitro and in vivo experiments have suggested that the drug directly inhibits calcium resorption from bone; however, the overall effects of gallium nitrate on calcium balance were unknown. We have completed metabolic balance studies in four patients who received this drug by prolonged infusion. All patients were in positive calcium balance while receiving the drug. Each patient also showed a substantial decrease in urinary calcium excretion. Serum phosphorus decreased in all four patients. There was no change in phosphorus, sodium, chloride, or magnesium balance or in creatinine clearance. We conclude that prolonged infusions of gallium nitrate reduce urinary calcium excretion and that the hypocalcemic effect of this drug is primarily due to inhibition of calcium resorption from bone. Thus, the drug may prove useful in reducing accelerated bone resorption in patients with bone metastases or chronic cancer-related hypercalcemia.

Administration of gallium nitrate by continuous infusion: lack of chronic nephrotoxicity confirmed by studies of enzymuria and beta 2-microglobulinuria.

Enzymuria and beta 2-microglobulinuria are sensitive markers of injury to renal tubular cells. We evaluated these markers in 41 patients with advanced malignant lymphoma who received gallium nitrate administered as a continuous infusion during a recent phase I-II study. In contrast to our findings with cisplatin, we observed no significant increase in enzyme excretion or beta 2-microglobulinuria in these patients even after long-term treatment. Our results indicate that gallium nitrate administered by infusion does not produce cumulative renal tubular toxicity.