Effects of cisplatin on parathyroid hormone- and human lung tumor-induced bone resorption.

We have previously shown that dichlorodiamine platinum (DDP), or cisplatin, a cancer chemotherapeutic agent, is effective in the treatment of malignancy-associated hypercalcemia. In the present studies, we evaluated its effects on bovine parathyroid hormone (PTH)- or tumor-induced bone resorption in vitro in the neonatal mouse calvarial bone resorption assay. PTH alone or tumor extract (TE) of a human squamous cell lung cancer alone caused a significant increase in the bone resorption and in the number of osteoclasts in the calvaria. The addition of 3 and 10 micrograms/ml DDP inhibited the PTH- or TE-induced bone resorption. Lower doses of 1 and 2 micrograms/ml DDP, although not effective in inhibiting the PTH-induced bone resorption, were effective in lowering the TE-induced bone resorption. The number of osteoclasts was also reduced by DDP treatment. We therefore conclude that DDP is effective in the treatment of malignancy-associated hypercalcemia by virtue of its inhibitory effects on osteoclast numbers and on bone resorption.

Treatment of cancer-associated hypercalcemia with cisplatin.

Cisplatin (cis-platinum) has been shown to lower cancer-associated humoral hypercalcemia in an animal model and to inhibit bone resorption in vitro. This prospective study was designed to evaluate the efficacy of cisplatin in treating cancer-associated hypercalcemia in humans. Thirteen patients with severe hypercalcemia refractory to rehydration were treated with a 24-hour infusion of cisplatin, 100 mg/m2. Serial measurements of serum calcium and tumor size were made following cisplatin treatment and compared with pretreatment values. Nine patients (69%) achieved normocalcemia after treatment with cisplatin; and mean duration of benefit was 38 days in these patients. No reduction in tumor size was seen. All patients died of progressive cancer. We conclude that cisplatin can control malignant hypercalcemia for relatively long periods, and that its mechanism of action is not due to a reduction in tumor size.

A phase II study of Adriamycin in previously untreated squamous cell carcinoma of the head and neck.

Twenty patients with squamous cell carcinoma of the head and neck (SCC H/N) were treated with Adriamycin (doxorubicin) at a dosage of 60 mg/m2 at 3-week intervals. No patient had received surgery, radiation, or chemotherapy before treatment with Adriamycin. Responses were observed in 44% of 18 evaluable tumors. We conclude that Adriamycin is a highly active drug in SCC H/N when no prior treatment has been administered.

Cis-platinum treatment for malignancy-associated humoral hypercalcemia in an athymic mouse model.

We have established a model for malignancy-associated humoral hypercalcemia (MAHH) in athymic mice, utilizing a human squamous cell lung carcinoma. In the present studies, we evaluated cis-platinum (DDP), a cytotoxic agent known to produce hypomagnesemia, and occasionally hypocalcemia, in the treatment of MAHH. Upon development of significant hypercalcemia, defined as serum calcium (Ca) greater than or equal to 11.5 mg/dl, tumor-bearing mice received either normal saline (NS) alone (1.5 ml/day, i.p.), or NS + DDP. The DDP was given as a single dose of 6 micrograms/g body weight i.p. Serum Ca was determined on day 6 in surviving mice (6 of 10 survived in the NS-alone group; 7 of 10 survived in the NS + DDP group). Serum Ca (mean +/- SE) decreased from 14.3 +/- 0.46 to a nadir of 12.7 +/- 0.33 mg/dl in the NS-alone group, and from 13.5 +/- 0.46 to a nadir of 10.4 +/- 0.48 mg/dl in the NS + DDP group. Nadir serum Ca levels were significantly lower in the NS + DDP group (P = 0.003). Three of 7 surviving NS + DDP mice achieved normocalcemia, whereas none of the NS-alone animals became normocalcemic. Tumor volumes increased in all animals. There was no change in the serum Ca in 5 tumor-free mice treated with NS + DDP. There were no significant differences in serum magnesium levels among groups of control mice, tumor-free mice treated with NS + DDP, tumor-bearing mice treated with NS + DDP, and tumor-bearing mice treated with NS-alone.(ABSTRACT TRUNCATED AT 250 WORDS)

A model for malignancy-associated humoral hypercalcemia.

Tumor tissue from a patient with squamous cell carcinoma of the lung and hypercalcemia has been serially implanted into athymic mice. Tumor-bearing mice develop cachexia, hypercalcemia without bone metastases, hypophosphatemia, increased urinary cyclic adenosine monophosphate (cAMP) to creatinine ratio, and undetectable human immunoreactive parathyroid hormone levels. Radiographs of spines in the tumor-bearing mice demonstrate demineralization, suggesting skeletal resorption as the source of the hypercalcemia. Within 4-8 hours following tumor removal, hypercalcemia is reversed, suggesting that a relatively short-acting humoral substance is responsible for the hypercalcemia. The animals gain weight and become essentially normal within 4 days following tumor removal. The studies demonstrate that this animal model is similar in many aspects to human malignancy-associated humoral hypercalcemia (MAHH) and can provide a useful tool for further investigation of the pathogenesis and treatment of this syndrome.

Preirradiation chemotherapy for advanced head and neck carcinomas.

Twenty-six patients with locally advanced squamous cell carcinoma of the head and neck region were treated with combination chemotherapy (cisplatin, bleomycin sulfate, and vincristine sulfate) prior to radiotherapy (RT). The chemotherapy produced a 65% major response rate, all partial responses. Significant hematologic toxic effects occurred in only two patients and severe renal toxic effects were not seen. Concurrently, 20 additional patients with locally advanced cancers were treated with high-dose RT along. Weight loss at the completion of RT and normal tissue reactions were similar in both groups. Complete tumor resolution occurred in 45% of RT-alone patients and 42% of patients completing combined-modality therapy. No difference in recurrence-free survival was seen. Despite minimal additional morbidity and a high response rate, this preirradiation chemotherapy regimen demonstrated no major impact on complete response rate or on long-term recurrence-free survival.

Acute vascular episodes associated with therapy for carcinomas of the upper aerodigestive tract with bleomycin, vincristine, and cisplatin.

Twenty-nine patients were treated for carcinoma of the head and neck with a combination of cisplatin, vincristine, and bleomycin. Four of these patients had acute vascular episodes (three had cerebrovascular accidents and one developed Raynaud's phenomenon) during or after treatment. Two additional patients with a similar history and course are also included for analysis. Three of these six patients had known underlying cardiovascular disease, which may have been a contributing risk factor. A reinstitution of bleomycin infusion produced a recurrence of the Raynaud's phenomenon in the patient who had developed that toxic effect.

Immediate versus postponed combination chemotherapy (CAMP) for unresectable non-small cell lung cancer: a randomized trial.

A randomized control trial was performed in good performance status patients with unresectable non-small cell lung cancer to test a strategy of early aggressive combination chemotherapy (CAMP [cyclophosphamide, doxorubicin, methotrexate, and procarbazine]) versus a strategy of delaying such treatment until clinical deterioration. Thirty-seven patients received immediate CAMP and 35 patients received initial low-dose single-agent CCNU (CAMP was postponed). Immediate CAMP therapy produced an objective response rate of 44% in patients with measurable lesions, and CCNU produced none. Median survival was 193 days for the immediate-CAMP group and 175 days for the postponed-CAMP group (P = 0.26). Measures of quality of life were made and no difference emerged between the two treatment strategies. This trial failed to show substantial benefit from immediate combination chemotherapy in minimally symptomatic patients with non-small cell lung cancer.