A randomized comparison of high-dose infusion methotrexate versus standard-dose weekly therapy in head and neck squamous cancer.

Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospectively controlled study comparing high-dose infusion methotrexate with leucovorin against standard-dose methotrexate without leucovorin. Patients were stratified for prior treatment and hematogenous metastases prior to randomization. Patients received either methotrexate (1,500 mg/m2) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly. Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity. After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly. One patient was ineligible and four had inadequate follow-up to assess response (less than two weeks). Forty-two patients were evaluable for survival and 37 for response. Six of 19 patients (32%) treated with high-dose infusion responded (one complete response) and four of 18 patients (22%) receiving standard dosage responded (P = .52). Treatment with high-dose methotrexate resulted in an improved duration of disease control over standard dosage with the respective median times to progression of 11 weeks and five weeks (P = .04). These differences were most marked in good performance status patients (P = .007) and those without hematogenous dissemination (P = .02). Toxicity, however, was also significantly worse in the high-dose treatment group (P = .01) and survival was identical between treatments (4.2 months). The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival. Good performance status patients may benefit from more aggressive therapy.

Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused over 72 hours in phase II studies.

A novel derivative of camptothecin, 9-aminocamptothecin (9-AC), is currently under Phase II evaluation in various cancers. Exceptionally mild toxicities were observed in patients with brain tumors who were treated with anticonvulsants. To investigate a pharmacokinetic interaction between 9-AC and anticonvulsants, and to evaluate the pharmacodynamics of 9-AC, we investigated the clinical pharmacology of 9-AC, administered by a 72-h infusion, in three Phase II studies. Plasma concentrations of total 9-AC (lactone plus carboxylate) at a steady state were measured in 56, 10, and 14 patients with non-small cell lung cancer, malignant glioma, and head and neck cancer, respectively. For lung cancer or glioma patients, 9-AC was infused at 45 (51 patients) or 59 (15 patients) microg/m2/h, and 9-AC was infused at 35.4 microg/m2/h in head and neck cancer patients. All glioma patients had been treated with phenytoin or carbamazepine. 9-AC clearance did not differ among the dosage rates, but differed according to the diseases (P = 0.002). Glioma patients had a higher clearance (1.0-18.0; median, 2.0 liters/h/m2) than lung cancer patients (0.3-5.1; median, 0.9 liters/h/m2). A logistic regression model described the relationship between the 9-AC concentration and the probability of grade 4 neutropenia, which was the main toxicity. Observed incidences of grade 4 neutropenia for patients with model-predicted probability of 0-20%, 20-40%, and 40-100% were 10%, 32%, and 67%, respectively, and corresponded to 9-AC concentration of <54, 54-86, and >86 ng/ml, respectively. Anticonvulsants seem to induce the clearance of 9-AC, and the concentration of 9-AC predicts the probability of grade 4 neutropenia.

Treatment of hypercalcemia of malignancy with intravenous etidronate. A controlled, multicenter study. The Hypercalcemia Study Group.

In a prospective, randomized, double-blind, multicenter study, 202 patients with cancer from 19 medical centers were treated for hypercalcemia of malignancy with daily intravenous infusions of etidronate disodium (136 patients) or saline alone (66 patients) for 3 consecutive days. Patients also received up to 3.25 L of saline daily during the treatment period. Of 157 patients for whom data could be evaluated for efficacy, 63% (72/114) of etidronate-treated and 33% (14/43) of saline-treated patients had a normalization of total serum calcium levels. When serum calcium levels were adjusted for albumin (147 assessable patients), 24% of the etidronate- and 7% of the saline-treated patients responded to treatment. No serious side effects or treatment-related deaths occurred. When accompanied by adequate hydration and diuresis, intravenous etidronate was safe and more effective than hydration and diuresis alone in controlling hypercalcemia of malignancy.

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.

Effect of epidermal growth factor infusion on serum and urine calcium in mice.

Transforming growth factors (TGFs) have been implicated in the pathogenesis of the hypercalcemia in malignancy (HM). In order to evaluate the role of these growth factors (epidermal growth factor (EGF) and TGF-alpha acting via the EGF receptor) in the development of HM, we studied the effect of 2 doses of EGF (0.1 and 0.3 microgram/g/day) given for 7 days as a continuous infusion on serum and urine calcium in athymic mice. These infusions had no effect on serum and urine Ca values in this study. In order to assess the biological activity of the infused EGF, other known effects on gastric and pancreatic weights were evaluated. EGF-infused animals had significantly greater gastric and pancreatic weights than controls. Thus, EGF infusion into mice in doses which elicited known biological effects failed to have an effect on serum and urine Ca. An infusion of bovine parathyroid hormone 1-34 at the dose of 0.1 microgram/g/day resulted in significant hypercalcemia.

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.

Elevated nephrogenous cyclic AMP with normal serum parathyroid hormone levels in patients with lung cancer.

Total and nephrogenous urinary cyclic AMP (cAMP), serum Parathyroid Hormone (PTH) and ionized calcium (Ca) levels were determined in 8 normal subjects, and 16 normocalcemic and 9 hypercalcemic patients with lung cancer. Total and nephrogeneous cAMP levels were significantly increased in both normocalcemic and hypercalcemic lung cancer patients, as compared to normal subjects. There was no significant correlation between serum PTH and total or nephrogenous cAMP in the cancer group. The factors responsible for the elevated nephrogenous cAMP in the lung cancer patients are not known.

Development of skeletal metastasis by human prostate cancer in athymic nude mice.

The biology of skeletal metastasis is poorly understood. In order to establish an animal model of bone metastasis, cells from a human prostate cancer cell line (PC-3) were injected into the tail veins of athymic nude mice while the inferior vena cava was occluded. This technique was used in order to divert cells into the vertebral venous plexus. A control group of animals received tumor cells without caval occlusion. Bone lesions developed in 3/16 (19 per cent) experimental mice and in none of the control mice. The incidence of lung metastasis was significantly decreased in the experimental mice (5/16) as compared with non-occluded control mice (14/16). Two tumor sublines were established from explant cultures of bone lesions. Injection of these cells resulted in bone metastasis in 19/36 (53 per cent) mice (P = 0.03 compared with the parent line). The incidence of lung lesions was also increased. The predominant site of bone metastasis was the lumbar vertebrae; other affected sites were the pelvis and femurs. All bone lesions resulted in extensive bone destruction. The successful development of bone metastasis using the technique of caval occlusion lends support to the hypothesis that entry of cells into the vertebral circulation is an important step in the development of these lesions. This model should be of value in understanding the pathogenesis of bone metastasis, and in studying the effects of various agents on the prevention and control of these lesions.

Presence of prostaglandin E in lung tumors from normocalcemic patients.

Prostaglandin E levels were determined in the tumor and normal lung tissue in 14 normocalcemic patients with lung cancer. All of the tested extracts from tumor and normal lung tissue revealed the presence of prostaglandin E; the levels were significantly higher in tumor tissue as compared with normal lung tissue. All of the tested tissue culture media from the tumors and all but one of those tested from normal lung revealed the presence of prostaglandin E; the levels were significantly higher in tumor tissue as compared with normal lung. There was no correlation between the level of prostaglandin E production and subsequent development of hypercalcemia or bone metastases or the duration of survival. The studies suggest that production of prostaglandin E by the tumors is a common phenomenon even in normocalcemic patients, and therefore its presence in the tumor tissue from a hypercalcemic patient may not necessarily implicate prostaglandin E in the pathogenesis of hypercalcemia in that patient.

Postsurgical adjuvant therapy in stages I, II, and IIIA non-small cell lung cancer.

The prognostic importance of accurate staging of non-small cell lung cancer was established in 1974 and reaffirmed and refined in 1986. The concept of adjuvant therapy after pulmonary resection for lung cancer is justified by the behavior of the disease. The best available data pertinent to adjuvant therapy of lung cancer have been collected by The Lung Cancer Study Group over the past 13 years. These data are based on a commitment to prospective and standardized surgical staging as a basis for large-scale prospective randomized control trials. A treatment effect of combination chemotherapy has been detected for stage II and IIIA nonsquamous cancer and is suggested for squamous cancer as well. This treatment effect is of marginal clinical significance. Adjuvant therapy for stage I disease has not shown a detectable benefit. Adjuvant radiation therapy for stage II and IIIA squamous cell carcinoma likewise has not resulted in survival benefit. Systemic metastasis continues to be the major clinical problem in lung cancer treatment, and better systemic therapy is necessary to improve the outcome in this disease. However, some patients do benefit from adjuvant chemotherapy, and efforts to identify such patients prospectively are also the subject of current clinical research.

Autopsy findings in squamous-cell carcinoma of the esophagus.

The findings at autopsy of 79 patients with esophageal carcinoma over a period of 15 years were reviewed. Five patients were free of tumor, and another seven had disease localized to the esophagus and other mediastinal structures. Sixty-seven (85%) had metastatic disease. The average number of metastatic sites per patient was 3.3. Most common metastatic sites were lymph nodes (73%), lung (52%), and liver (47%). The patients in this series had a higher incidence of metastases than those in other published series. Possible reasons for this discrepancy include race and sex differences between this population and those in previous reports, as well as the fact that this series includes very few postoperative deaths.

Hypocalcemia in patients with prostate cancer.

We report a case of severe hypocalcemia in a patient with prostate cancer and extensive metastatic bone disease. The hypocalcemia in this patient was most likely on the basis of extensive accretion of calcium into the bones. We further studied 112 patients with prostate cancer, 15 of whom were discovered to be hypocalcemic on the basis of serum total calcium measurement. Fourteen of these 15 patients had bone metastases. Serum total calcium, total protein, and albumin levels were significantly lower in patients with bone metastases (n = 61) than those without (n = 51). Hypocalcemia could be explained on the basis of hypoalbuminemia or renal failure in these patients. Plasma ionized Ca measurements were made in 47 of the total 112 patients. Only one patient with extensive bone metastases was found to be hypocalcemic on the basis of ionized calcium measurement. Therefore, apparent hypocalcemia based on total calcium measurement is common in patients with prostate cancer (14% of all and 23% of those with bone metastases), whereas true hypocalcemia based on ionized calcium determinations is unusual.

Cisplatin nephrotoxicity in a patient with a single kidney.

OBJECTIVE: To describe a patient with a single kidney who experienced cisplatin-associated nephrotoxicity. CASE SUMMARY: A 78-year-old African-American woman with squamous cell carcinoma of the base of her tongue (T4N2M1) was admitted electively to our institution for the first cycle of chemotherapy. Her past medical history was significant for a left nephrectomy secondary to well-differentiated papillary transitional cell carcinoma of the left renal pelvis, hypothyroidism, asthma, and coronary artery disease. Her blood urea nitrogen (BUN) was 27 mg/dL of urea, and serum creatinine was 1.2 mg/dL. On admission she was hydrated adequately, and was treated with an evening dose of cisplatin 100 mg/m2 (180 mg) in 250 mL of NaCl 0.9% solution in a 3-hour infusion, and a 5-day course of fluorouracil 1000 mg/m2 (1800 mg) in a 24-hour infusion. Serum creatinine and BUN concentrations following cisplatin administration were 1.1 mg/dL and 8 mg/dL, respectively. Four days after cisplatin therapy, a decline in renal function was observed, with an increase in serum creatinine and BUN concentrations to 4.0 mg/dL and 31 mg/dL, respectively. These tests remained elevated throughout her hospitalization. With hemodialysis treatments a resolution in altered mental status was observed; however, her chronic renal failure persisted. She was subsequently discharged and followed in the outpatient renal, geriatric, and oncology clinics. DISCUSSION: Cisplatin is a principal chemotherapeutic agent used in the treatment of a variety of solid tumors. Nephrotoxicity is a major complication associated with this compound. Although many clinicians believe that cisplatin nephrotoxicity is unlikely to occur in patients with a single kidney, recent reports have suggested otherwise. The physiologic changes of the aging kidney are such that they should foster cisplatin clearance rather than expose the kidney to the drug's nephrotoxic potential. In addition, evening administration of cisplatin is thought to minimize nephrotoxicity. We describe a 78-year-old woman with a single kidney who developed nephrotoxicity following a single evening dose of cisplatin. Details of the patient's history and cisplatin-associated complication and therapy are discussed. CONCLUSIONS: Cisplatin circadian rhythmic pharmacotherapy to minimize cisplatin toxicity in patients with a single kidney appears to be controversial and needs further evaluation.

Taste thresholds of patients with cancer of the esophagus.

Twelve patients with untreated cancer of the esophagus and 14 control subjects matched for age, smoking, and alcohol consumption were tested for taste thresholds. Taste acuity for the four basic tastes was evaluated by three stimulus forced choice techniques (Henkin). There were no significant differences between the groups for detection and recognition thresholds for sour, salty, sweet, or bitter taste stimuli. Comparison of patients' detection and recognition thresholds with those of eight young healthy nonsmokers showed marked differences. Salivary urea nitrogen concentration was not different between patients and matched controls and did not correlate with bitter taste thresholds. Variable results have been reported for taste sensitivity in patients with malignant disease. In view of the results of this study and the many factors which influence taste acuity, it appears that a general statement regarding taste alterations in cancer patients cannot be made. Choice of appropriate control groups to correct for factors known to affect taste but not related to cancer per se is important for proper interpretation of taste testing results.

A specific HPLC assay to determine the pharmacokinetics of methotrexate in patients.

The pharmacokinetics of methotrexate and its metabolite, 7-hydroxymethotrexate (7-OH-MTX), were evaluated by a specific HPLC assay in patients receiving low dose (40 mg/m2) or high dose (750-1500 mg/m2) MTX. A wide range of total body clearance (1.03-5.13 ml/min/kg) was obtained in four subjects. The apparent renal clearances of MTX and 7-OH-MTX were found to decline with increasing serum levels, indicating the existence of saturable tubular secretion for the drug. The steady-state volume of distribution of MTX was 0.41-0.95 l/kg. Urinary excretion of MTX was almost complete at 36-48 h after dosing. The nonrenal excretion accounted for 17-39% of the dose. Extensive formation of 7-OH-MTX occurred at all dose levels, with their serum levels being 2.4- to 10-fold higher than MTX levels 24 h post infusion. The mean apparent renal clearance of 7-OH-MTX (0.08-0.13 ml/min/kg) was much smaller compared with that of MTX (0.63-2.62 ml/min/kg). The average saliva/serum level ratios were 0.009 and 0.078 in two patients studied.

Nephrogenous cyclic adenosine monophosphate levels in normocalcemic cancer patients: its significance.

We evaluated nephrogenous cyclic adenosine monophosphate ( NcAMP ) levels in 61 normocalcemic patients with documented cancer of various organs and cell types. NcAMP levels were elevated in 17 (28%) and decreased in 13 (21%) of the cancer patients. Both high and low NcAMP levels were seen within the various cancer groups. There was a significant correlation (r = 0.383, P less than 0.01) between NcAMP and serum parathyroid hormone (PTH) levels, suggesting that tumor-related factors affecting NcAMP , may be partially related to native PTH. Alternatively, these factors might be altering the effect of endogenous PTH on renal tubules. A significant negative correlation was also observed between NcAMP and tubular maximum for phosphate (r = -0.356, P less than 0.02) suggesting that either cAMP per se or factors affecting NcAMP alter phosphate excretion. Follow up serum calcium data was available on 48 of the 61 patients. Subsequent hypercalcemia developed independent of the initial nephrogenous cAMP levels. It therefore appears that NcAMP elevation and development of hypercalcemia are two separate paraneoplastic phenomena.

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.

High-dose aminothiadiazole in advanced colorectal cancer. An Illinois Cancer Center phase II trial.

Thirty-three patients with advanced colorectal carcinoma were entered on a phase II trial of weekly IV aminothiadiazole (175 mg/m2 escalated to 200 mg/m2) with concomitant allopurinol and non-steroidal anti-inflammatory agents (NSAID's). Toxicity was predominantly GI, cutaneous, and chest pain/dyspnea. Twenty-five percent of patients had grade 3 or 4 toxicity. There were no responses in 27 evaluable patients. Median survival was 12 months. Aminothiadiazole, at higher doses than used in previous reports, when given with NSAID's, had no significant activity against large bowel cancer.

Phase II trial of spirogermanium in advanced non-small cell lung cancer. An Illinois Cancer Council Study.

A phase II trial of spirogermanium was conducted in advanced previously untreated non-small cell lung cancer patients. The drug was given by intravenous infusion 3 times per week for 2 weeks, twice per week for the next 2 weeks, and then weekly. Starting dose was 125 mg/m2, and dose escalation of 25 mg/m2 per week was required in the absence of toxicity to a maximum dose of 200 mg/m2 per infusion. Fifteen eligible patients were treated, and no objective responses were seen. Primary toxicity was neurologic and reversible after withdrawal of the drug. We conclude that spirogermanium is not active against non-small cell lung cancer in the dosage used in this study.

Phase II trial of fludarabine phosphate in advanced renal cell carcinoma: an Illinois Cancer Council Study.

Fludarabine Phosphate (FP), the 2-fluoro, 5'phosphate derivative of adenosine arabinoside (ara-A), was studied in 18 patients with advanced renal cell carcinoma. These patients had measurable disease and had not received chemotherapy. FP was administered at a loading dose of 20 mg/m2 followed by a 48-hour infusion at 30 mg/m2/day given every 21 days. There were no complete or partial responses seen. Toxicity was mainly hematologic, with leukopenia most commonly observed. FP given in this manner had no activity in advanced renal cell carcinoma.