Randomized trial of aminoglutethimide versus tamoxifen in metastatic breast cancer.

We compared antiestrogen therapy (tamoxifen) with an estrogen suppression regimen (aminoglutethimide-hydrocortisone) in postmenopausal women with metastatic breast carcinoma. Fifteen of 39 patients (38%) who received tamoxifen experienced an objective tumor regression (3 complete, 12 partial remissions), whereas 13 of 36 women (36%) receiving aminoglutethimide responded (one complete remission, 12 partial remissions). The median duration of response was similar. The site of tumor involvement appears to be important in choosing between these hormonal treatments. Aminoglutethimide appears to offer a greater chance of response in patients with bone involvement.

Cross-over comparison of tamoxifen and aminoglutethimide in advanced breast cancer.

Thirty-four postmenopausal patients with advanced breast cancer had an overall objective response rate of 47% when treated with aminoglutethimide and hydrocortisone initially and a response rate of 24% when crossed over to therapy with tamoxifen after progression on aminoglutethimide. A similar group of 32 patients experienced a response rate of 28% when treated with tamoxifen first and a 19% objective response rate on subsequent therapy with aminoglutethimide. Patients who failed to respond to the first therapy seldom responded on cross-over to the alternate therapy. Toxicities were acceptable with both forms of therapy. Tamoxifen and aminoglutethimide used sequentially are effective forms of palliative hormonal therapy in metastatic breast cancer.

Corynebacterium parvum versus bacille Calmette-Guérin adjuvant immunotherapy of stage II malignant melanoma.

Two separate studies have been reported comparing Corynebacterium parvum and bacille Calmette-Guérin (BCG) as adjuvant immunotherapy for stage II melanoma patients (The Milton S. Hershey Medical Center, 48 patients; Southeastern Cancer Study Group [SECSG], 162 patients). As the criteria for patient selection and drugs used were similar, we have pooled the data to analyze the effects of these two treatments. Both studies used BCG (Tice, Chicago, IL) 3 x 10(8) live organisms per treatment by Tine technique and C parvum (Burroughs-Wellcome, Triangle Park, NC) subcutaneous at a dose of 4 mg/m2 (SECSG) or 5 micrograms/m2 (Hershey) per treatment. The only difference in these studies was the frequency of immunization, with patients in Hershey receiving 22 doses and the SECSG patients receiving 55 doses during the 2-year period of treatment. Kaplan-Meier life-table analysis for the 210 patients shows a prolonged disease-free interval for patients treated with C parvum (P = .02, two-sided Mantel procedure). In similar fashion, patients treated with C parvum had an improved survival rate (from all causes) when compared with BCG-treated patients (P = .012). An analysis of the results for the 170 patients for which the number of positive nodes was available was performed using Cox's model, with nodes as a stratification variable and with covariates of place, treatment, age, and sex. In this analysis, an observed benefit for C parvum on the disease-free interval had a P value of .37 while the benefit of C parvum on the survival times (from all causes) had a P value of .04. When the same analysis was performed using only patients aged younger than 60 years, the observed benefit of C parvum on disease-free interval had a P value of .08 and the benefit of C parvum on survival times (from all causes) had a P value of .008.

Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen.

PURPOSE: To determine the effect of elevated serum HER-2/neu on the response of metastatic breast cancer patients to an aromatase inhibitor versus an antiestrogen. PATIENTS AND METHODS: Five hundred sixty-two estrogen receptor-positive metastatic breast cancer patients were randomized to first-line hormone therapy with either letrozole or tamoxifen. An automated enzyme-linked immunosorbent assay was used to detect serum HER-2/neu. RESULTS: For patients with normal serum HER-2/neu (70.5%), objective response rate (ORR; 39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P =.008), clinical benefit (CB; 57% v 45%; P =.016), time to progression (TTP; median, 12.2 v 8.5 months; P =.0019), and time to treatment failure (TTF; median, 11.6 v 6.2 months; P =.0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group (29.5%), there was no significant difference in ORR (17% in letrozole-treated patients v 13% in tamoxifen-treated patients; P =.45) or CB (33% v 26%; P =.31), but there was a strong trend in favor of a longer TTP with letrozole (median, 6.1 v 3.3 months; P =.0596) and a significantly longer TTF with letrozole (median, 6.0 v 3.2 months; P =.0418). Multivariate analysis revealed that elevated serum HER-2/neu was a negative predictor for ORR and TTP. CONCLUSION: Patients with normal serum HER-2/neu receiving letrozole demonstrated a significantly greater ORR and CB and longer TTP and TTF than patients receiving tamoxifen. Although in patients with elevated serum HER-2/neu there was no significant difference between letrozole and tamoxifen in ORR or CB, there was a strong trend favoring longer TTP and significantly longer TTF with letrozole.

Medical castration produced by the GnRH analogue leuprolide to treat metastatic breast cancer.

Leuprolide (Lupron, TAP Pharmaceuticals, North Chicago), a gonadotropin-releasing hormone analogue, was administered to 26 premenopausal women with metastatic breast cancer. Of 25 evaluable patients, 11 (44%) had a partial response with a median duration of 39 weeks and five (20%) remained stable. Six patients showed early rapid progression of their disease. Toxicity was mild and included hot flashes, nausea, vomiting, and headache. Leuprolide induced amenorrhea in all patients who received treatment for ten weeks or longer. We conclude that this GnRH analogue provides a safe and effective means of producing medical castration in premenopausal patients with metastatic breast carcinoma.

Epidermal growth factor receptor ectodomain in the urine of patients with squamous cell carcinoma.

In this study we determined the levels of the epidermal growth factor receptor (EGFR) in the urine of patients with squamous cell carcinoma compared to levels in the urine of normal volunteers and patients with nonsquamous cell carcinoma. A 24-h urine specimen was collected from 50 normal volunteers, 50 patients with nonsquamous cell carcinoma, and 42 patients with squamous cell carcinoma. An ELISA using mAbs to the external domain of the EGFR was used to measure levels of the receptor in the urine samples. Measurement of the EGFR ectodomain in the 24-h urine specimens showed detectable levels in 15 (36%) of 42 squamous cell carcinoma patients compared to 3 (6%) of 50 controls and 8 (16%) of 50 nonsquamous patients. It was also observed that 10 (53%) of 19 patients with metastatic squamous cell carcinoma had detectable EGFR ectodomain levels compared to 5 (22%) of 23 squamous cell patients with localized disease. Thus, we concluded that the EGFR ectodomain was detectable in the urine in a significantly higher number of patients with squamous cell carcinoma than normal volunteers or patients with nonsquamous cell carcinoma.

Maintenance etidronate in the prevention of malignancy-associated hypercalcemia.

Normocalcemic patients with cancer who had been successfully treated for an episode of hypercalcemia were enrolled in a randomized, multisite, double-blind, placebo-controlled trial designed to determine the efficacy of maintenance oral etidronate in preventing the recurrence of moderate to severe hypercalcemia (serum calcium level, greater than 11.5 mg/dL [greater than 2.87 mmol/L]). Ten (40%) of 25 etidronate-treated patients and 17 (46%) of 37 placebo-treated patients had recurrence of hypercalcemia within 150 days. Although patients taking etidronate had a longer time to the development of hypercalcemia (median, 55 days vs 28 days), this was not significantly different from the control group. The high attrition rate in this trial from hypercalcemia and other malignancy-related causes represents a major difficulty in conducting studies with agents that may require prolonged administration before producing a therapeutic effect.

Use of aromatase inhibitors in breast carcinoma.

Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.

The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis.

The family of cytochrome P450 enzymes that mediates steroid hydroxylations are distinct but structurally related proteins. Inhibitors of these steroidogenic steps generally exhibit only relative and dose-related specificity. We evaluated an imidazole, cytochrome P450-related inhibitor, CGS 16949A, in postmenopausal patients with metastatic breast cancer. While a relatively specific aromatase inhibitor at daily dosages of 1-2 mg, CGS 16949A significantly blunted cortisol responses to ACTH at a dose of 16 mg daily. To further evaluate other inhibitory effects of this drug, we determined blood levels of aldosterone (ALDO) and 18-hydroxycorticosterone and their respective urinary metabolites, tetrahydroaldosterone and tetrahydro-18-hydroxy-11-dehydrocorticosterone in 16 postmenopausal women receiving CGS 16949A. At a dose of 16 mg/day, CGS 16949A produced significant (P less than 0.001) suppression of both basal and ACTH-stimulated ALDO production. This was accompanied by a significant rise in the blood 18-hydroxycorticosterone/ALDO ratio (11.4 +/- 0.19; normal, less than 2; P less than 0.001), consistent with a corticosterone methyloxidase type II inhibition. A similar significant elevation (7.5 +/- 1.2; normal, less than 5; P less than 0.001) in the urinary tetrahydro-18-hydroxy-11-dehydrocorticosterone/tetrahydroaldosterone ratio was also observed. These results suggest that CGS 16949A is a potent inhibitor of the corticosterone methyloxidase type II enzyme at a dose of 16 mg daily. At doses of 1-2 mg daily, CGS 16949A blocks aromatase without altering basal aldosterone production and, thus, exhibits dose-related specificity.

Aromatase inhibitors in clinical practice: current status and a look to the future.

Aromatase inhibitors are a new class of agents that are of considerable interest for potential use as palliative therapy for hormone-dependent metastatic breast cancer in postmenopausal women. In the postmenopausal or castrate female, the process of aromatization accounts for the majority of circulating, biologically active estrogens. This report presents a clinical perspective on some of the most recent information concerning the biology and pharmacology of the aromatase enzyme and highlights the development of newer aromatase inhibitors with important therapeutic potential. Clinical questions addressed include the selection of aromatase inhibitors, the selection of the most appropriate patients for therapy with these new agents, and the positioning of these new agents with respect to other forms of endocrine therapy for breast cancer. Finally, we shall consider areas for future investigation of possible new indications for these agents in clinical medicine.

Clinical usefulness of 67gallium scanning in the malignant lymphomas.

To determine the clinical usefulness of 67 gallium (Ga) scanning in the evaluation of patients with lymphomas, we reviewed 142 total body Ga scans performed on 44 patients with Hodgkin's disease and 53 patients with non-Hodgkin's lymphoma. Fifty-two per cent (123 of 236) of known disease sites were detected on scan. The false-positive rate was less than 5 per cent. The accuracy of detecting lymphoma varied in individual anatomic areas from 33 per cent in the axilla to 73 per cent in the thorax. In eight patients with bone involvement, all bone lesions were detected on scan. The size of the lesion appeared to influence accuracy, since tumors greater than 3 cm in diameter were more often positive.

The effects of long term fadrozole hydrochloride treatment in patients with advanced stage breast cancer.

Fadrozole hydrochloride at a dose of 2 mg b.i.d. has been shown to be an effective aromatase inhibitor in advanced stage breast cancer patients as determined by its ability to significantly suppress endogenous estrogen biosynthesis over a 12-week period. Continued suppression of circulating estrogen levels over a prolonged period has not yet been examined in published reports. In this study, we report the extended use of fadrozole hydrochloride at a maintenance dose of 2 mg b.i.d. in a cohort of 11 patients extending to 973 days of therapy. Results show that the degree of suppression of plasma and urinary estrogens was maintained in all patients throughout the extended period of drug use. Continued estradiol suppression of over 50% or greater from baseline was observed, as was continued suppression of estrone to over 80% from baseline. Cortisol determinations after 9 months of treatment showed no suppression from baseline. The aldosterone values and responses to cortrosyn stimulation continued to be suppressed as first noted following the initial 3 months of the core clinical trial. Objective tumor response noted in the core clinical trial did not change until disease progression. These findings suggest that fadrozole hydrochloride maintains its ability to suppress the aromatase enzyme during long term use. No observable escape from suppression of plasma and urinary estrogens occurred during prolonged treatment.

The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with advanced stage breast cancer.

The pharmacologic inhibition of aromatase activity has been the focus of clinical trials in patients with advanced stage breast cancer. Recent developments with imidazole compounds that inhibit aromatase activity suggest their clinical use as potent inhibitors of estrogen biosynthesis in postmenopausal breast cancer patients. In this Phase I, open-label, dose-range finding study, we examined the inhibitory potency of CGS 20267 on blood and urine levels of estradiol, estrone and estrone sulfate in 8 patients with metastatic breast cancer. Studies included evaluation of adrenal and thyroid function to look for evidence of general hydroxylase inhibition at dose levels effective for aromatase blockade. Patients were administered CGS 20267 at doses of 0.1 and 0.25 mg, once a day in ascending doses over a 12-week period. Preliminary data reveal that CGS 20267 elicits a striking suppression in plasma estradiol, estrone and estrone sulphate which was observed in some patients as quickly as within 24 h of the first dose. Estrogen suppression of over 90% was achieved within 2 weeks of therapy. No alterations in either baseline or ACTH (cortrosyn) stimulated cortisol and aldosterone levels were observed through the 12 weeks of therapy. In addition, 24 h urine sodium and potassium values were not appreciably altered during therapy. We conclude that CGS 20267 is a potent, specific inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic breast cancer and effectively reduces blood and urine estrogens to undetectable levels.

Somatostatin analogues in the treatment of breast and prostate cancer.

Newly developed somatostatin analogues may be useful agents in the treatment of breast and prostate cancer. Potential mechanisms of antitumor action include suppression of circulating levels of trophic hormones and growth factors as well as direct effects at the tumor level, potentially involving autocrine/paracrine mechanisms. Pilot clinical trials conducted in heavily pretreated women with advanced breast cancer indicate that SMS 201-995 (Sandostatin R) has minimal toxicity and moderately suppresses stimulated growth hormone secretion and basal somatomedin-C level. Somatostatin analogues have also been found to retard the growth of experimental prostate cancer, particularly when used in combination with LHRH analogues. The therapeutic efficacy of these compounds used alone or in combination with other agents in the treatment of breast and prostate cancer remains to be established in larger clinical trials involving less heavily pretreated patients.

FAM chemotherapy +/- aminoglutethimide in the treatment of pancreatic carcinoma.

Human pancreas contains receptors for estrogens and androgens as well as aromatase activity. FAM chemotherapy was administered to 14 patients with pancreatic cancer (seven at Stage IV). The median survival of these patients was 24.4 +/- 4.8 weeks. FAM chemotherapy plus aminoglutethimide/hydrocortisone (AG/HC) (250 mg bid AG + 20 mg bid HC) was administered to 14 patients (seven at stage IV). The median survival of this group was 17.3 +/- 2.9 weeks (P = 0.74 vs FAM alone). We conclude that addition of AG/HC does not add to the survival of patients with carcinoma of the pancreas treated with chemotherapy.

Growth inhibition of breast cancer cell lines by combinations of anti-P185HER2 monoclonal antibody and cytokines.

The p185HER2 oncogene is associated with poor prognosis in patients with breast cancer. Both anti-p185HER2 MAb and cytokines have been shown to downregulate p185HER2 expression. We investigated the effect of combinations of humanized 4D5, and anti-p185HER2 MAB, and the cytokines IFN-alpha, IFN-gamma or TNF-alpha on the growth of three p185HER2 positive human abreast carcinoma cell lines, SK-BR-3, BT-474, and MDA-MB-453. All three cell lines were treated with IFN-alpha (1000 U/ml) or IFN-gamma (1000 U/ml) or TNF-alpha (100 U/ml) with or without huMAb 4D5 (100 microM), and cell growth was determined on days 3-7. While IFN-alpha, IFN-gamma, TNF-alpha, and huMAb 4D5 all inhibited growth, an apparently additive inhibitory effect occurred using combinations of huMAb 4D5 plus cytokine, with huMAb 4D5 plus TNF-alpha causing the greatest growth inhibition. These results demonstrate the potentiation of growth inhibition of breast cancer cell lines by the combination of anti p185HER2 MAb and cytokines, and suggest that combinations of anti-growth factor receptor MAb and cytokines may be useful in the treatment of breast cancer.

Emerging role of aromatase inhibitors in the treatment of breast cancer.

The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme aromatase act by decreasing estrogen production throughout the body in postmenopausal women. The most potent of these agents may also inhibit estrogen synthesis within metastatic breast cancer tissue. The newly developed, orally administered, nonsteroidal competitive inhibitors, such as anastrozole (Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times more potent inhibitors of aromatase than is aminoglutethimide. Furthermore, these agents are highly selective. In several large randomized trials, the new inhibitors produced similar response rates as megestrol acetate (160 mg/d) in postmenopausal women with hormone-dependent breast cancer, but showed a trend toward improved response duration and survival. They also produced less weight gain and fewer cardiovascular and thromboembolic side effects. In addition, letrozole proved superior to aminoglutethimide in another randomized trial. Both anastrozole (1.0 mg/d) and letrozole (2.5 mg/d) have now been approved as second-line treatment for hormone-dependent breast cancer in postmenopausal women in whom disease has progressed following tamoxifen treatment. Either drug should replace the routine use of megestrol acetate in this setting. Ongoing clinical studies are comparing anastrozole and letrozole to antiestrogens as first-line endocrine therapy for metastatic breast cancer. Other trials will study the possible roles of these compounds as adjuvant therapy and chemoprevention for breast cancer.

Aerodigestive tract papillomatosis: bacille Calmette-Guérin (BCG) immunotherapy.

Aerodigestive tract papillomatosis (ADTP) remains a distinct challenge for the otolaryngologist. None of the myriads of therapies utilized to date offers a distinctly improved prognosis with less frequent clinical recurrences or absolute cure rates. Significant complications are avoided by withholding tracheotomy whenever possible and avoiding overly aggressive papilloma removal. Laser technology seems to offer a distinct benefit as regards the latter. Despite much activity in this area, little new knowledge has actually influenced the outcome of patients afflicted with papillomatosis. The disorder remains one of long-term morbidity in those acquiring it early in life and one with a significant rate of mortality for those with involvement of the lower airway. A review and selected discussion of our experience at The Milton S. Hershey Medical Center of The Pennsylvania State University with ADTP from 1974 to 1981 is presented. Nineteen patients ranging in age at the time of presentation from 1.5 to 68 years old have been diagnosed and treated. For the most part, therapy consisted of repeated microendoscopies with forceps removal of papillomas until recurrences ceased. However, in four adult patients with either rapidly recurring laryngeal and/or tracheobronchial papillomas, bacille Calmette-Guérin (BCG) immunotherapy has been administered. Two of these patients are evaluable for greater than 12 months. The rationale and efficacy of the treatment of a high risk group in this fashion are discussed.

Cis-platinum ototoxicity: clinical experience and temporal bone histopathology.

A clinical and pathologic study of cis-platinum ototoxicity was performed. Twenty-four patients treated with cis-platinum for head and neck cancer were studied prospectively. Post cis-platinum hearing losses were subclinical, detected in 25% of patients, isolated to 4 and 8 kHz, and did not exceed 25 dB at any frequency. Temporal bones from a 9-year-old with frontal lobe astrocytoma and with cis-platinum ototoxicity were studied with routine and special techniques to elucidate oto and neurotoxicity. Degenerative changes in the outer hair cells in the lower turns of the cochlea, in the spiral ganglion, and cochlear nerve were the most striking findings.

Phase I study combining tumor necrosis factor with interferon-alpha and interleukin-2.

We evaluated the effects of the addition of escalating doses of tumor necrosis factor (TNF) to two fixed doses and schedules of a combination of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) to determine the maximum tolerated dose of this three-cytokine combination and its feasibility as an outpatient regimen. Eighteen patients with metastatic cancer were enrolled. Each course consisted of 3 consecutive weeks of treatment with IFN-alpha 9 x 10(6) IU/m2/day intramuscularly (i.m.) or subcutaneously (s.c.) days 1, 3, and 5 each week for 3 weeks plus IL-2 continuous infusion 1 x 10(6) IU/m2/day (group A) or 3 x 10(6) IU/m2/day (group B) days 1-5 each week for 3 weeks. TNF was administered only during the first week of each course intravenously (i.v.) for 2 h on days 1-5. The dose of TNF was escalated (40, 80, 120 micrograms/m2) in cohorts of 3 patients. The most common side effects were fever, chills, and fatigue in all patients. Grade 3-4 toxicity included anemia (3 patients), thrombocytopenia (1 patients), arrhythmia (2 patients), pulmonary edema (3 patients),- and weight loss (1 patient). Five patients withdrew from study due to toxicity. The combination of the three cytokines is feasible as an outpatient regimen in one of the following combinations: (a) TNF 80 micrograms/m2/day as 2-h infusion on days 1-5 + IL-2 1 x 10(6) IU/m2/day continuous infusion on days 1-5 for 3 weeks + IFN-alpha 9 x 10(6) IU/m2/day s.c. or i.m. on days 1, 3, and 5 for 3 weeks, or (b) TNF 40 micrograms/m2/day as a 2-h infusion on days 1-5 + IL-2 3 x 10(6) IU/m2/day continuous infusion on days 1-5 for 3 weeks + IFN-alpha 9 x 10(6) IU/m2/day s.c. or i.m. on days 1, 3, and 5 for 3 weeks.