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Background: Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer., Methods: NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1-3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00009945., Findings: Median follow-up was 90·7 months (IQR 82·7-100·0) and 3311 patients had data for this period. Disease-free survival did not differ between groups (286 events in the clodronate group vs 312 in the placebo group; hazard ratio 0·91, 95% CI 0·78-1·07; p=0·27). Moreover, no differences were recorded for overall survival (0·84, 0·67-1·05; p=0·13), recurrence-free interval (0·83, 0·67-1·04; p=0·10), or bone metastasis-free interval (0·77, 0·55-1·07; p=0·12). Non-bone metastasis-free interval was slightly increased with clodronate (0·74, 0·55-1·00; p=0·047). Analyses in women age 50 years or older on study entry showed benefits of clodronate for recurrence-free interval (0·75, 0·57-0·99; p=0·045), bone metastasis-free interval (0·62, 0·40-0·95; p=0·027), and non-bone metastasis-free interval (0·63, 0·43-0·91; p=0·014), but not for overall survival (0·80, 0·61-1·04, p=0·094). Adherence to treatment at 3 years was 56% for the clodronate group and 60% for the placebo group. Grade 3 or higher liver dysfunction was noted in 23 of 1612 patients in the clodronate group and 12 of 1623 patients in the placebo group; grade 3-4 diarrhoea was noted in 28 patients in the clodronate group and in ten in the placebo group. There was one possible case of osteonecrosis of the jaw in the clodronate group., Interpretation: Findings of NSABP B-34 suggest that bisphosphonates might have anticancer benefits for older postmenopausal women. A meta-analysis of adjuvant bisphosphonate trials is suggested before recommendations for use in non-osteoporotic postmenopausal women with primary breast cancer are made., Funding: National Cancer Institute, Bayer Oy (formerly Schering Oy)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Patient-reported outcomes (PROs), such as symptom scales or more broad-based health-related quality-of-life measures, play an important role in oncology clinical trials. They frequently are used to help evaluate cancer treatments, as well as for supportive and palliative oncology care. To be most beneficial, these PROs must be relevant to patients and clinicians, valid, and easily understood and interpreted. The Patient-Reported Outcomes Measurement Information System (PROMIS) Network, part of the National Institutes of Health Roadmap Initiative, aims to improve appreciably how PROs are selected and assessed in clinical research, including clinical trials. PROMIS is establishing a publicly available resource of standardized, accurate, and efficient PRO measures of major self-reported health domains (eg, pain, fatigue, emotional distress, physical function, social function) that are relevant across chronic illnesses including cancer. PROMIS is also developing measures of self-reported health domains specifically targeted to cancer, such as sleep/wake function, sexual function, cognitive function, and the psychosocial impacts of the illness experience (ie, stress response and coping; shifts in self-concept, social interactions, and spirituality). We outline the qualitative and quantitative methods by which PROMIS measures are being developed and adapted for use in clinical oncology research. At the core of this activity is the formation and application of item banks using item response theory modeling. We also present our work in the fatigue domain, including a short-form measure, as a sample of PROMIS methodology and work to date. Plans for future validation and application of PROMIS measures are discussed.

Accurate mapping of the aortic aneurysm in relation to the renal artery is pivotal in the success of abdominal aortic aneurysm repair. Currently, contrast computed tomography (CT), a method of combining both angiography and CT scan, is being used in the evaluation and diagnosis of abdominal aortic aneurysm. We report a series of cases in which contrast CT alone gave us misleading information on the true nature of the aneurysm in relation to the renal arteries. We conclude that the three-dimensional spiral CT reconstructed model provides better morphologic information for clinical decision-making than contrast CT alone.

Fourteen patients with squamous cell carcinoma of the head and neck received 9-AC/DMA infusions of 850 mg/M2/day over 72 hours. Eligibility criteria included good performance status, advanced disease incurable by conventional means, no prior treatment of metastatic disease, and measurable lesions for objective response assessment. The infusions were repeated at 21 day intervals until progression or prohibitive toxicity occurred. A median of 3 cycles (range 1-7) was given. No objective responses were observed. Median survival of the group was 6 months. Toxicity was hematologic which was modest and promptly reversible. 9-AC/DMA is inactive against this tumor type at the dose and schedule employed in this study.

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.

Background: 9-Aminocamptothecin (9-AC) is a synthetic analogue of camptothecin. Phase I studies, identified the maximum tolerated dose as 1416 micrograms/m2/day x 3 as continuous intravenous infusion (CVI) with dose-limiting neutropenia., Patients and Methods: Eligible patients had stage IIIB or IV non-small-cell lung cancer (NSCLC) with measurable disease. Patients were initially treated at 1416 micrograms/m2/d x 3 by CVI followed by granulocyte-colony stimulating factor (G-CSF) support. This dose was decreased to 1100 micrograms/m2/d after the first 13 patients. Cycles were repeated every 14 days until tumor progression., Results: Fifty-eight patients were treated, thirteen at 1416 micrograms/m2/d and 45 at 1100 micrograms/m2/d. Fifty percent had adenocarcinoma and 17% squamous cell carcinoma. Seventy-one percent had stage IV disease. Five patients had a partial response (response duration 9-28 weeks) for an overall response rate of 8.6%, (95% confidence intervals (CI): 2.9%-19%). Median time to progression was 2.3 months and the median survival for the entire study population 5.4 months with a one-year survival rate of 30%. The one-year survival rate for 27 patients who received second line chemotherapy was 56.7%. Toxicities at 1416 micrograms/m2/d included grade 4 neutropenia and thrombocytopenia in six and five of 13 patients, respectively; at 1100 micrograms/m2/d these toxicities were observed in 12 and three of 45 patients, respectively., Conclusion: 9-AC has modest single-agent activity in previously untreated NSCLC. Its further evaluation at the dose and schedule employed in this study does not seem indicated. Exploration of more prolonged administration schedules may be warranted.

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.

Purpose: The purpose of this study is to determine whether primary treatment with both radiotherapy and chemotherapy is superior to radiotherapy alone in patients with squamous cell carcinoma of the esophagus., Patients and Methods: From January 1980 to December 1988, 77 patients from two Veterans Affairs hospitals with clinically staged nonmetastatic squamous cell carcinoma of the esophagus received either radiotherapy alone (RT group) or concomitant radiotherapy and chemotherapy (RT + CT group) with curative intent. Each group originated at a different hospital, but all patients were irradiated in the same radiotherapy department. Chemotherapy consisted of cisplatin and 5-fluorouracil. Forty-two patients received RT alone, and 35 received RT + CT. Locoregional control, disease-free survival, and overall survival rates were compared., Results: Locoregional control, disease-free survival, and overall survival rates were significantly higher in the RT + CT group when compared to RT group, 26% vs 5%, 20%, vs 2%, and 29% vs 7%, respectively, at 2 years (P = .01, 0.02 and 0.02, respectively). The median survival was 14 months for the RT + CT group and 7.5 months for the RT group. There was no difference in the incidence of distant metastases except for bone metastases. No one in the RT + CT group developed bone metastases compared to nine patients in the RT group (P = .01)., Conclusion: This retrospective analysis shows improved locoregional control, disease-free survival, and survival when chemotherapy consisting of cisplatin and 5-FU is given in addition to radiation for patients with squamous cell carcinoma of the esophagus. Bony metastases were absent in those who received chemotherapy.

Amonafide (nafidimide), a synthetic organic compound with an inhibitory effect on cellular replication, was used in a phase II study conducted by the Illinois Cancer Center in order to assess its efficacy and toxicity in advanced or recurrent squamous cell cancer of the head and neck. Eligible patients had received no more than one prior adjuvant or neoadjuvant chemotherapy, had normal bone marrow, renal and hepatic function, ECOG performance status of 0-2, and bidimensionally measurable disease. Eligible patients were administered amonafide at a starting dose of 300 mg/m2 for five consecutive days every 3 weeks with dose escalation or de-escalation according to established hematologic criteria in the absence of disease progression. Nineteen of 22 entered patients were evaluable for response and all patients were evaluable for toxicity. Eleven of 19 patients achieved stable disease. Median time to progression after start of treatment was 57 days, for the 18 patients for whom the date of progression is known. There were no partial or complete responses. Hematologic toxicity was dose limiting with grade 3-4 neutropenia in 50 percent of patients and 4 deaths associated with neutropenic sepsis. Non-hematologic toxicity was mild to moderate with nausea and vomiting predominating. In this study, amonafide was a myelotoxic, inactive treatment in advanced/recurrent head and neck cancer. Further use in head and neck cancer appears unwarranted.

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.

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.

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.

A phase II trial of 4' Deoxydoxorubicin (DXDX) was conducted in unresectable previously untreated non-small cell lung cancer patients. DXDX was administered every 3 weeks by short intravenous infusion at a starting dose of 30 mg/m2, with dose escalation to 40 mg/m2 toxicity permitting. Four responses, all partial, were observed in 35 evaluable patients, for a response rate of 11% (95% confidence limits 3.2% and 26.7%). Myelosuppression was the dose-limiting toxicity. Cardiotoxicity was not seen. DXDX has minimal activity against non-small cell lung cancer as a single agent at the dosage used in this study.

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.

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.

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.

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.

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.

A clinico-pathologic study of 173 patients with esophageal cancer was done. The median survival for all patients was 6.4 months. Persistent tumor in esophagus at the time of death was present in 78% of patients treated with radiation alone. Metastases to mediastinal, intraabdominal and supraclavicular nodes were found in 73%, 49% and 20% of patients respectively. Systemic metastases were found in 57% of patients, liver being the most common site. In 15% of patients, fistulae developed between esophagus and trachea or bronchus because of direct extension of the primary tumor. Local and regional tumor caused the death of 111 patients, whereas distant metastases led to death in only 27 patients. This study confirms the extensive intra- and extrathoracic spread of malignancy in a majority of patients with cancer of the esophagus.

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.

The purpose of this study was to compare the effect of post-operative thoracic radiation with or without systemic chemotherapy on survival and recurrence patterns in patients subjected to thoracotomy with curative intent, but subsequently found to have residual tumor in the resected margin or metastasis in the highest paratracheal lymph node. All patients were treated with postoperative mediastinal irradiation and randomized to receive or not receive combination chemotherapy (cytoxan, adriamycin, and platinum) for 6 months beginning concurrently with radiation. Of the 172 patients randomized, 164 were eligible for analysis. The mean time since randomization for the eligible patients is 4.2 years. Radiation therapy was administered to all patients by split course regimen [20 Gy in 5 fractions over 5 days]. Two such courses were given with a 3-week interval. The initial recurrence rates for both in-field recurrence and distant relapse were reduced in the combined postoperative radiation therapy and chemotherapy group, although only the latter difference achieved statistical significance (p = 0.01). Also, local recurrence overall (not restricted to initial recurrences) is examined as a function of histology, extent of residual disease after resection, and T and N status. The treatment effect achieves statistical significance only for patients with macroscopic residual (p = .023) or T3 tumor (p = .010). The combined therapy group of patients have a significantly longer recurrence-free survival [p = 0.006 by the two-sided Mantel-Haenszel logrank test] which fails, however, to translate to a significant difference in overall survival (p = 0.146). Median survival of the entire group is 14.5 months with 34% alive 2 years after resection. Most of the initial recurrences (82%) have been systemic, with brain being the most common site. Distant failure, therefore, remains an important problem even in the favorable prognosis subset of patients with advanced NSCLC, but combined modality approaches can produce improved recurrence-free survival.

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.

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.

Experience with camp chemotherapy of 84 unresectable non-oat cell lung cancer patients is described. Fourteen (27%) of 51 patients with measurable lesions responded (3 CR, 11 PR) for a median response duration of 5 months with a range of 1 to 19+ months. Median survival of responders was 370 days, but response was not independent of performance status. Survival of patients without measurable lesions was less favorable than that of even nonresponders, suggesting prediction of response to CAMP by site of metastasis. Preliminary results of a randomized prospective trial of the CAMP combination versus CCNU as a single agent for patients with good performance status fail to show a difference in survival.

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.

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 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.

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.