Treatment of metastatic renal cell carcinoma with coumarin (1,2-benzopyrone) and cimetidine: a pilot study.

Forty-five patients with metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) and cimetidine. Patients received coumarin, 100 mg orally daily; cimetidine administration, 300 mg orally four times daily, was initiated on day 15 of therapy, and treatment with both drugs was continued until progression of disease. Three patients are too early to evaluate (on study less than or equal to 2 months with no change in tumor status). Objective responses (greater than or equal to 50% reduction in measurable disease) occurred in 14 of 42 evaluable patients (33.3%) (the 95% confidence interval based on this rate is +/- 14.3%), with three complete responses and 11 partial responses (PR). Complete responses lasted 9.5, 4+, and 9.5+ months. The median duration of response for the PR group was 5 months (range, 4 to 21+ months). Twelve patients experienced stabilization of disease ranging from 4 to 16.5+ months. No response was seen in 16 patients. There was no symptomatic, hematologic, or chemical (organ dysfunction) toxicity among the 45 patients treated. Coumarin and cimetidine appear to be safe and active agents in the treatment of metastatic renal carcinoma. Further studies are required to determine the optimal dose and scheduling of these agents.

Extended administration of oral etoposide and oral cyclophosphamide for the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.

PURPOSE: We designed an all-oral regimen of etoposide and cyclophosphamide for use in advanced non-small-cell lung cancer. PATIENTS AND METHODS: Eligible patients were chemotherapy-naive and had histologically confirmed assessable or measurable stage IV non-small-cell lung cancer. Patients received etoposide 50 mg/m2/d orally days 1 through 14 and cyclophosphamide 50 mg/m2/d orally days 1 through 14 every 28 days. Doses on later cycles were adjusted for myelosuppression. RESULTS: Sixty-six patients (64 eligible patients) received 192 cycles of oral extended etoposide/cyclophosphamide therapy (median, two cycles; range, zero to 15). Therapy was well tolerated with the mean dose per cycle being 104% of the originally scheduled dose. Two patients (3%) achieved a complete response and six (9%) achieved a partial response. Leukopenia, anemia, nausea/vomiting, and alopecia were the most common toxicities. Median survival was 6 months, and the 1-year survival rate was 25.6%, comparable to more intensive treatments. CONCLUSION: Oral extended etoposide/cyclophosphamide is a well-tolerated alternative for the treatment of stage IV non-small-cell lung cancer and can be used as a basis for the design of further outpatient regimens.

Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone.

PURPOSE: Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer (HRPC). A prospective randomized clinical trial was designed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant, opioid analgesic-dependent pain. PATIENTS AND METHODS: A double-blind, placebo-controlled trial randomized patients to receive a 78-day, outpatient regimen of either suramin plus hydrocortisone (HC, 40 mg/d) or placebo plus HC. Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred; placebo patients were allowed to cross-over to open-label suramin plus HC. In addition to pain and opioid analgesic intake, prostate-specific antigen (PSA) response, time to disease progression, quality of life, performance status, and survival were compared. RESULTS: Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC (rank sum P =.0001). Pain response was achieved in a higher proportion of patients receiving suramin than placebo (43% v 28%; P =.001), and duration of response was longer for suramin responders (median, 240 v 69 days; P =.0027). Time to disease progression was longer (relative risk = 1.5; 95% confidence interval, 1.2 to 1.9) and the proportion of patients with a greater than 50% decline in PSA was higher (33% v 16%; P =.01) in patients who received suramin. Neither quality of life nor performance status was decreased by suramin treatment, and overall survival was similar. Most adverse events were of mild or moderate intensity and were easily managed medically. CONCLUSION: Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC.

Coumarin (1,2-benzopyrone) for the treatment of prostatic carcinoma.

The unavailability of effective treatment for metastatic hormone-refractory and clinically localized but pathologically unfavorable prostatic carcinoma warrants trial of new and promising treatments. Preliminary studies in patients with metastatic disease have shown (a) subjective but no objective responses to 100 mg coumarin and cimetidine daily; (b) objective responses in 3 of 40 patients treated with 3 g coumarin daily, all of whom had normal performance status and 1 of whom remains with three resolved bone metastases and stable prostate-specific antigen levels after 4 years; (c) toxicity only in bedridden patients. We recently initiated two multi-center trials of 1 g coumarin daily. Metastatic prostatic carcinoma patients of normal performance status were treated in a phase II trial. Patients who had been treated by radical prostatectomy, but had surgical margin, seminal vesicle or lymph node involvement or detectable prostate-specific antigen after radical prostatectomy, were randomized to coumarin or placebo.

Growth-inhibitory effects of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin on human malignant cell lines in vitro.

Coumarin (1,2-benzopyrone) is a natural substance that has shown antitumor activity in vivo. The major human metabolite of coumarin, 7-hydroxycoumarin (7-HC), is the active form of the drug. While the exact mechanism(s) of action of coumarin is unknown, it has been shown previously that this drug possesses immunomodulatory activity in vitro and in vivo. The present investigations examined the direct (non-immunological) antitumor effects of coumarin and 7-HC in vitro. Both coumarin and 7-HC were found to be growth-inhibitory (cytostatic) for the following human malignant cell lines: A549, ACHN, Caki-2, Dakiki, HS-Sultan, H727, HCT-15, HL-60, K562, LNCaP, PC-3, Du 145 COLO-232, MCF-7 and RP-1788. The growth inhibition was dependent on dose and time and was reversible upon removal of cells from medium containing the drug. Coumarin and 7-HC inhibited [3H]thymidine, [3H]uridine and [3H]leucine incorporation. In a similar fashion, coumarin and 7-HC inhibited the intracellular production of prostate-specific antigen by LNCaP cells. Coumarin and 7-HC stimulated apoptosis in HL-60 cells but not in other cell lines tested. It is concluded that coumarin and 7-HC have direct antitumor (cytostatic) activity as well as immunomodulatory activity. Further information is needed in order to determine which activities are responsible for antitumor activity in vivo.

An updated review of the clinical development of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin.

Several authors have demonstrated that coumarin (1,2-benzopyrone) in combination with cimetidine can produce objective antitumor responses in some patients with advanced renal cell carcinoma. The purpose of this report is to review the clinical development of coumarin, with or without cimetidine, with special reference to renal cell carcinoma (RCC). Previously unpublished data concerning the survival of a population of patients with RCC, who were treated on a phase I trial of coumarin and cimetidine, are presented. The rationale and study design of an active randomized, double-blinded, placebo-controlled trial of coumarin for RCC are discussed. A progress report is given for an ongoing phase I trial of oral 7-hydroxycoumarin, the major human metabolite of coumarin.

Low incidence of asymptomatic brain metastases in patients with renal cell carcinoma.

Brain metastases from renal cell carcinoma are uncommon. The present study was undertaken to determine the value of routine computerized tomographic (CT) scanning of the brain in patients with renal cell carcinoma. A review of 106 patients with renal cell carcinoma who had undergone CT scan of the brain revealed brain metastases in only 13.2 percent. Brain metastases were accompanied by central nervous system (CNS) symptoms in 78.6 percent of patients, with headaches constituting the most common presenting symptom (64.3%). Brain metastases were detected in only 3.3 percent of patients who had no CNS symptoms at the time of evaluation. It is concluded that CT scanning of the brain should be performed routinely only for those patients who report CNS symptoms at the time of evaluation.

Treatment of advanced malignant melanoma with coumarin and cimetidine: a pilot study.

Based on previous results demonstrating that coumarin and cimetidine render objective tumor regressions in renal cell carcinoma, we conducted a pilot study to determine whether these drugs possess activity against malignant melanoma. A total of 22 patients with advanced melanoma received 100 mg coumarin p.o. daily for 14 days; on day 15, cimetidine was added at an oral dose of 300 mg four times daily. Both drugs were continued until progression of disease. In all, 12 patients had previously been treated, but all patients had a favorable performance status. No response was observed in 19 patients. Two patients with a low tumor burden achieved a partial response and a third showed a minor response. There was no toxicity from this regimen. Although coumarin and cimetidine at this dose and schedule did not display significant activity in this study population, further studies are warranted to explore higher doses and focus on patients with relatively low tumor burdens.

Cutaneous involvement in malignant histiocytosis. Case report and review of the literature.

Malignant histiocytosis (MH) is a rare, malignant neoplasm with protein manifestations, including fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, and, infrequently, cutaneous lesions. A patient had initial manifestations that included fever and skin lesions. Skin lesions began on distal areas of the extremities and spread to involve proximal areas of the extremities and the abdomen. Erythematous maculopapular lesions, nodules, and plaques were present in various stages of development, which evolved into ulcerated plaques that exuded a serosanguineous discharge. Spontaneous healing of lesions occurred, leaving hyperpigmented, atrophic scars. Histologically, the deep dermis and subcutaneous tissues contained a diffuse infiltrate of histiocytes, lymphocytes, and mononuclear cells. Erythrophagocytosis by histiocytes was present in the skin biopsy material. Thirteen percent of 320 cases in the literature had skin involvement. This report and review of the literature indicate that, in selected cases, skin biopsy may contribute to the diagnosis of MH.

Arteriovenous malformation simulating Kaposi's sarcoma (pseudo-Kaposi's sarcoma).

A patient whose condition was initially misdiagnosed as Kaposi's sarcoma involving the left foot received radiation therapy for that disorder. Subsequent examination yielded a correct diagnosis of arteriovenous (AV) malformation. Such cases of AV malformations with skin changes resembling Kaposi's sarcoma have been called pseudo-Kaposi's sarcoma. The clinicopathologic distinctions between Kaposi's sarcoma and pseudo-Kaposi's lesions are discussed. All patients suspected of having Kaposi's sarcoma, especially those younger than 30 years of age, should have careful evaluation for an unsuspected AV malformation.

Competitive and territorial fighting: two types of offense in the rat.

Two types of fighting (offense) were compared and contrasted in three experiments on the laboratory rat. In Experiment 1, competitive fighting was obtained in pairs of hungry cagemates by placing one food pellet into their food hopper. In Experiment 2, territorial fighting was obtained by introducing an unfamiliar intruder into the home cage of a male and female pair. Both types of fighting had the same motor patterns. Whereas territorial fighting is strongest against intruders of the same sex, competitive fighting is stronger against the smaller opponent (in this case female) regardless of the sex of the test animal. Whereas territorial fighting is stronger in males, competitive fighting is stronger in females. Whereas gonadectomy reduces territorial fighting in males but not females, it reduces competitive fighting in both sexes. In experiment three, it was shown that food deprivation increases competitive fighting, while it reduces territorial fighting. On the basis of these findings a revised model of the organization of the offense motivational system is proposed.

Phase II trial of amonafide for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group study.

Amonafide (benzisoquinolinedione; NSC 308847) was subjected to a Phase II trial for the treatment of advanced hormone-refractory carcinoma of the prostate. In addition to adequate baseline organ functions, patients were required to have a favorable performance status, bidimensionally measurable disease and no prior chemotherapy. Amonafide was given at a dose of 225 mg/m2 intravenously daily for 5 days. Treatment cycles were repeated every 21 days. Dose escalation and reduction schema were used based upon toxicities from preceding cycles. Of 47 patients enrolled, 43 were evaluable. The most common toxicities were hematologic to include leukopenia (72%), granulocytopenia (32.6%), and thrombocytopenia (44.2%). There were no complete responses and only 5 partial responses for an overall response rate of 12% (95% confidence interval: 4-25%). The results indicate that Amonafide, in the dose and schedule tested, lacks sufficient activity against hormone-refractory prostate cancer to warrant further trials.

Phase II trial of CHIP for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group Study.

CHIP, a second generation analogue of cisplatin, was subjected to a Phase II trial for the treatment of advanced, hormonally refractory carcinoma of the prostate. Forty-six patients were treated with CHIP 300 mg/m2 intravenously every 4 weeks. Evaluations for tumor response were done after three cycles of therapy. Among 40 evaluable patients there were no complete responses, but there were 6 partial responses for an overall response rate of 15% (95% confidence interval of 5.7 to 29.8%). The median time to response was 2.4 months and the median progression-free survival was 4.1 months. Median survival was 8.4 months. The most common toxicities were hematologic and gastrointestinal. While CHIP can be administered on an outpatient basis, its response rate for prostatic carcinoma appears to be similar to that of cisplatin.

Treatment of stage D2 hormone refractory carcinoma of the prostate with 5-fluorouracil and Roferon-A: a Southwest Oncology Group study.

Based upon prior data suggesting that alpha-interferon possesses chemomodulatory activity, the Southwest Oncology Group conducted a study in which patients with hormone refractory, metastatic (stage D2) adenocarcinoma of the prostate were treated with 5-fluorouracil (5-FU) and Roferon-A. All patients had bidimensionally measurable disease. Treatment consisted of 5-FU 750 mg/m2/day by continuous i.v. infusion for 5 days with Roferon-A 9 million units subcutaneously ono days 1, 3 and 5. Roferon-A was continued three times weekly throughout treatment. Following a one week hiatus from 5-FU (week 2), 5-FU was continued at a dose of 750 mg/m2 i.v. bolus weekly. Nineteen patients were evaluable for toxicity. The most common toxicities were gastrointestinal and mucosal, hematologic and a flu-like syndrome. There were no deaths related to treatment. Among the 14 patients evaluable for response, the response rate was 0% (95% confidence interval, 0-18%). Thirteen of the 19 evaluable patients have died with a median survival of 9 months. The combination of 5-FU and Roferon-A does not have sufficient activity against advanced, hormone refractory prostate cancer to warrant further investigation.

Cerebrospinal fluid cytology in histiocytic proliferative disorders.

Morphologically atypical histiocytes were observed in the cerebrospinal fluid (CSF) of five patients with histiocytic proliferative disorders, including one each classified as Letterer-Siwe disease and Hand-Schüller-Christian disease and three as malignant histiocytosis. In all of these patients except the one with Letterer-Siwe disease, neurologic examination, CSF leukocyte count and protein and glucose concentrations were normal. Necropsy studies in the three fatal cases (one patient with Letterer-Siwe disease and two with malignant histiocytosis) demonstrated leptomeningeal involvement by atypical histiocytes in all three and brain involvement in the patient with Letterer-Siwe disease. These observations suggest that cytologic examination of CSF is warranted in patients with histiocytic proliferative disorders and may be reliable in documenting central nervous system, particularly leptomeningeal, involvement. The atypicality of the histiocytes in the CSF, however, was not indicative of the classification of the histiocytic proliferative disorder. Because the patient with Hand-Schüller-Christian disease continues to have a normal neurologic examination seven years after abnormal histiocytes were initially detected in his CSF, we believe that the clinical condition of the patient and classification of the histiocytic proliferative disorder are of primary importance for initiating aggressive therapy directed at the central nervous system.